Heterocyclic Compounds Useful for Kinase Inhibition

ABSTRACT

Provided herein are compounds useful for kinase inhibition.

CROSS-REFERENCE

This patent application is a national phase application of PCTApplication serial number PCT/US2011/029879 filed on Mar. 24, 2011 andclaims the benefit of U.S. Provisional Patent Application No.61/317,223, filed Mar. 24, 2010, which applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Kinases regulate fundamental processes in cancer and otherhyperproliferative disorders including aspects such as proliferation,migration and metastasis, neovascularization, and chemoresistance.Accordingly, kinase inhibitors have been a major focus of drugdevelopment and several kinase inhibitors are now approved for variouscancer indications. Typically, kinase inhibitors are selected via highthroughput screening using catalytic kinase domains at low ATPconcentration and this process often yields ATP mimetics that lackspecificity and/or function poorly in cells where ATP levels are high.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a compoundhaving the structure (I) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide,or a pharmaceutically acceptable salt thereof:

wherein:

-   -   Q is O or S;    -   W is C₆-C₁₂ aryl or C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   each of X and Y is independently absent or a NH;    -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl;    -   Z₃ is O, S, N, or NR₅, wherein R₅ is hydrogen or lower alkyl;    -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   each R₂ and R₃ are independently selected from a group        consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms,        CF₃, halogen, CN, CONHR₆ and CO₂R′ wherein R′ is hydrogen or        C₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form a five        to seven membered carbocycle;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl; p=0-4; and n is 1 or 2.

In some embodiments, there is provided a compound having the structure(II) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or apharmaceutically acceptable salt thereof:

or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceuticallyacceptable salt thereof:wherein

-   -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl;    -   Z₃ is O, S, N, or NR₅, wherein R₅ is hydrogen or lower alkyl;    -   each R₂ and R₃ are independently selected from a group        consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms,        CF₃, halogen, CN, CONHR₆ and CO₂R′ wherein R′ is hydrogen or        C₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form a five        to seven membered carbocycle;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl; n is 1 or 2; and    -   R₈ and R₉ is independently selected from the group consisting of        hydrogen, halogen, optionally substituted C₁-C₆ alkyl, —CF₃,        —OH, optionally substituted C₁-C₆ alkoxy, —NR₁₀R₁₁, and        —SO_(m)R₁₂, wherein R₁₀ and R₁₁ are independently selected from        a group consisting of hydrogen, optionally substituted C₁-C₆        alkyl, —SO₂R₁₂, —S(O)R₁₂, and —COR₁₂, and R₁₂ is an optionally        substituted alkyl or an optional substituted C₃-C₁₂ heteroaryl        having 1-3 heteroatoms and m is 0-2.

In other embodiments, there is provided a compound having the structure(III) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or apharmaceutically acceptable salt thereof:

wherein

-   -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl; and    -   Z₃ is O, S, N, or NR₅, wherein R₅ is hydrogen or lower alkyl.    -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   each R₂ and R₃ are independently selected from a group        consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms,        CF₃, halogen, CN, CONHR₆ and CO₂R′ wherein R′ is hydrogen or        C₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form a five        to seven membered carbocycle;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl; p=0-4; and n is 1 or 2.

In some embodiments, there is provided a compound having the structure(IV) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or apharmaceutically acceptable salt thereof:

(IV)

wherein:

-   -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl;    -   Z₃ is O, S or NR₅, wherein R₅ is hydrogen or lower alkyl;    -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, —NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl and n is 1 or 2; and    -   R₁₃ is an optionally substituted N—(C₁-C₆ alkyl)pyrazolyl or        selected from a group consisting of the following structures:

In other embodiments, there is provided a compound having the structure(V) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceuticallyacceptable salt thereof:

wherein:

-   -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, —NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, and —CONR₆R₇, wherein R₆ and R₇ are        independently selected from a group consisting of hydrogen, and        an optionally substituted C₁-C₆ alkyl; n is 1 or 2; and    -   R₁₄ is selected from a group consisting of an optionally        substituted C₁-C₁₂ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, and an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms.

In some embodiments, there are provided methods for suppressing,preventing or inhibiting lymphangiogenesis, neovascularization,recruitment of periendothelial cells, angiogenesis, hyderproliferativedisorder, fibrotic lesion, ocular disorder and/or growth of a tumor. Themethods comprise contacting the tumor with a compound of structures I-Vor Ia-Va or a pharmaceutical composition comprising the compound ofstructures I-V or Ia-Va thereof.

In some embodiments, there are also provided methods for treatingcancer, restenosis, intimal hyperplasia, fibrotic diseases orangiogenesis-dependent disorder in a human subject. The methods compriseadministering to a patient in need a compound of structures I-V or Ia-Vaor a pharmaceutical composition comprising the compound of structuresI-V or Ia-Va thereof.

In certain embodiments, there are provided methods for preventinginhibition of ASK1-mediated apoptosis in a cell, sensitizing a cell toan extrinsic stress or inhibiting MEK1/2- and/or ERK1/2-mediatedcellular proliferation or migration. The methods comprise contacting thetumor with a compound of structures I-V or Ia-Va or a pharmaceuticalcomposition comprising the compound of structures I-V or Ia-Va thereof.

In some embodiments, there are provided methods of inhibiting a proteinkinase comprising contacting the protein kinase with an inhibitoryconcentration of a compound of structures I-V or Ia-Va or apharmaceutical composition comprising the compound of structures I-V orIa-Va thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

In the case of 1,2,4-triazoles, there exist three tautomeric structures,as shown below:

Which tautomeric structure is prevailing depends on the substituents onthe triazole moiety and on the reaction conditions. As known to thosehaving ordinary skill in the art, typically, 1H-1,2,4-triazole is themost common tautomeric form, especially if an amino substituent isattached to the ring. Even though all three tautomeric structures can bepresent and interconvert, all the generic structures and all theexamples having 1,2,4-triazole moiety are shown herein in one tautomericform, such as 4H-1,2,4-triazole, for simplicity and for the comparisonwith its direct analogues, such as examples containing 1,3,4-oxadiazolemoiety. Using only 4H-tautomeric form to draw the structures for thesake of simplicity, does not imply that the compounds provided hereinexist in that particular tautomeric form.

In accordance with the present invention, there are provided a compoundhaving the structure (I) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide,or a pharmaceutically acceptable salt thereof:

wherein:

-   -   Q is O or S;    -   W is C₆-C₁₂ aryl or C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   each of X and Y is independently absent or a NH;    -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl;    -   Z₃ is O, S, N, or NR₅, wherein R₅ is hydrogen or lower alkyl;    -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   each R₂ and R₃ are independently selected from a group        consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms,        CF₃, halogen, CN, CONHR₆ and CO₂R′ wherein R′ is hydrogen or        C₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form a five        to seven membered carbocycle;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl; p=0-4; and n is 1 or 2.

In accordance with the present invention, there are also provideddeuterium-enriched compounds having the structure (I) or an N-oxide,N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceutically acceptable saltthereof. The hydrogens present on the compounds of structure (I) havedifferent capacities for exchange with deuterium. Some are easilyexchangeable under physiological conditions (e.g. any acidic hydrogens)which may be changed during or after the synthesis of the finalcompounds. Some are not easily exchangeable and may be incorporated bythe use of deuterated starting materials or intermediates during theconstruction of the final compounds.

Some embodiments further provide a compound having the structure (I) oran N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceuticallyacceptable salt thereof, wherein Z₃ is O or S. In some embodiments, Q isS. In other embodiments, Q is O. In certain embodiments, n is 2. In someembodiments, W is C₃-C₁₀ heterocycle having 1-3 heteroatoms. In certainembodiment, W is selected from the group consisting of thiophene,pyridine, pyridazine, pyrimidine and pyrazine. For example, the compoundis selected from the group consisting of

In other embodiments, W is C₆-C₁₂ aryl. In certain embodiments, W isphenyl. In certain embodiments, Z₃ is O or S, and each R₂ and R₃ areindependently selected from a group consisting of a hydrogen, a C₁-C₆alkoxy, an optionally substituted C₁-C₆ alkyl, —CF₃, halogen, —CN, and—CO₂R′ wherein R′ is hydrogen or C₁-C₆ alkyl; or, optionally, R₂ and R₃are joined to form a five to seven membered carbocycle. In someembodiments, R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroarylhaving 1-3 heteroatoms. In certain embodiments, R₁ is an unsubstitutedor a substituted pyridine. In certain embodiments, R₁ is anunsubstituted pyridine or a C₁-C₆ alkyl substituted pyridine. In certainembodiments, R₁ is an unsubstituted or a substituted pyrimidine. In someembodiments, the compounds have the structure (I) wherein R₄ ishydrogen. In some embodiments, the compound have the structure (I)wherein each R₂ and R₃ are independently selected from a groupconsisting of a C₁-C₆ alkyl, —CF₃, and halogen, wherein p is 0 or 1 or2; or, optionally, R₂ and R₃ are joined to form a five to seven memberedcarbocycle.

In certain embodiments, the compound having structure (I) is selectedfrom the group consisting of

and the like.

In some embodiments, there are provided compounds having structure (I)selected from the group consisting of

and the like.

In some embodiments, there are provided compounds having structure (I)selected from the group consisting of

and the like.

In some embodiments, there is provided a compound having the structure(II) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or apharmaceutically acceptable salt thereof:

or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceuticallyacceptable salt thereof:wherein

-   -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl;    -   Z₃ is O, S, N, or NR₅, wherein R₅ is hydrogen or lower alkyl;    -   each R₂ and R₃ are independently selected from a group        consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms,        CF₃, halogen, CN, CONHR₆ and CO₂R′ wherein R′ is hydrogen or        C₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form a five        to seven membered carbocycle;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl; n is 1 or 2; and    -   R₈ and R₉ is independently selected from the group consisting of        hydrogen, halogen, optionally substituted C₁-C₆ alkyl, —CF₃,        —OH, optionally substituted C₁-C₆ alkoxy, —NR₁₀R₁₁, and        —SO_(m)R₁₂, wherein R₁₀ and R₁₁ are independently selected from        a group consisting of hydrogen, optionally substituted C₁-C₆        alkyl, —SO₂R₁₂, —S(O)R₁₂, and —COR₁₂, and R₁₂ is an optionally        substituted alkyl or an optional substituted C₃-C₁₂ heteroaryl        having 1-3 heteroatoms and m is 0-2.

In some embodiments, there are provided compounds having structure (II),wherein each R₂ and R₃ are independently selected from a groupconsisting of a hydrogen, a C₁-C₆ alkoxy, an optionally substitutedC₁-C₆ alkyl, —CF₃, halogen, —CN, and —CO₂R′ wherein R′ is hydrogen orC₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form a five toseven membered carbocycle. In some embodiments, R₄ is hydrogen. In someembodiments, R₈ and R₉ are independently selected from the groupconsisting of optionally substituted C₁-C₆ alkoxy, —NR₁₀R₁₁, and—SO_(m)R₁₂, and m is 0-2. In certain embodiment, R₈ is C₁-C₆ alkoxy or—SR₁₂. In some embodiments, each R₂ and R₃ are independently selectedfrom a group consisting of a C₁-C₆ alkyl, —CF₃, and halogen wherein p is0 or 1 or 2; or, optionally, R₂ and R₃ are joined to form a five toseven membered carbocycle.

Another embodiment provides the compound of structure (II), wherein R₂and R₃ are independently selected from a group consisting of a hydrogen,a C₁-C₆ alkoxy, an optionally substituted C₁-C₆ alkyl, —CF₃, halogen,—CN, and —CO₂R′ wherein R′ is hydrogen or C₁-C₆ alkyl.

In certain embodiments, the compound having the structure (II) isselected from the group consisting

and the like.

In some embodiments, there are provided compounds having the structure(II) selected from the group consisting of

and the like.

In some embodiments, there are provided compounds having the structure(II) selected from the group consisting of

and the like.

In other embodiments, there is provided a compound having the structure(III) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or apharmaceutically acceptable salt thereof:

wherein

-   -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl; and    -   Z₃ is O, S, N, or NR₅, wherein R₅ is hydrogen or lower alkyl.    -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   each R₂ and R₃ are independently selected from a group        consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms,        CF₃, halogen, CN, CONHR₆ and CO₂R′ wherein R′ is hydrogen or        C₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form a five        to seven membered carbocycle;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl; p=0-4; and n is 1 or 2.

In some embodiments, the compounds have the structure (III), where Z₃ isO or S. In some embodiments, each R₂ and R₃ are independently selectedfrom a group consisting of a C₁-C₆ alkyl, —CF₃, and halogen wherein p is0 or 1 or 2; or, optionally, R₂ and R₃ are joined to form a five toseven membered carbocycle. In some embodiments, R₁ is an unsubstitutedor a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms. For example,R₁ is an unsubstituted or a substituted pyridine. In certainembodiments, R₁ is an unsubstituted pyridine or a C₁-C₆ alkylsubstituted pyridine. In other embodiments, R₁ is an unsubstituted or asubstituted pyrimidine. In some embodiments provide the compound havingthe structure (III) where R₄ is hydrogen.

Another embodiment provides the compound having the structure of formula(III), wherein

-   -   R₂ and R₃ is independently selected from a group consisting of a        hydrogen, a C₁-C₆ alkoxy, an optionally substituted C₁-C₆ alkyl,        —CF₃, halogen, —CN, and —CO₂R′ wherein R′ is hydrogen or C₁-C₆        alkyl; and    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, —NO₂, —CN, C₁-C₆ alkoxy,        —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆, —S(O)₂R₆, —CO₂R₆, and        —CONR₆R₇, wherein R₆ and R₇ are independently selected from a        group consisting of hydrogen, and an optionally substituted        C₁-C₆ alkyl and n is 1 or 2. In some embodiments, R₂ and R₃ are        independently selected from a group consisting of a hydrogen, a        C₁-C₆ alkoxy, an optionally substituted C₁-C₆ alkyl, —CF₃,        halogen, —CN, and —CO₂R′ wherein R′ is hydrogen or C₁-C₆ alkyl;        and R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, —NO₂, —CN, C₁-C₆ alkoxy,        —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆, S(O)₂R₆, —CO₂R₆, and        —CONR₆R₇, wherein R₆ and R₇ are independently selected from a        group consisting of hydrogen and an optionally substituted C₁-C₆        alkyl.

In certain embodiments, the compound having structure (III) is selectedfrom the group consisting of

In some embodiments, the compound having the structure (III) is

or selected from the group consisting of

In some embodiments, there is provided a compound having the structure(IV) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or apharmaceutically acceptable salt thereof:

(IV)

wherein:

-   -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl;    -   Z₃ is O, S or NR₅, wherein R₅ is hydrogen or lower alkyl;    -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, —NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl and n is 1 or 2; and    -   R₁₃ is an optionally substituted N—(C₁-C₆ alkyl)pyrazolyl or        selected from a group consisting of the following structures:

In some embodiments, the compound have structure (IV), where n is 2. Insome embodiments, Z₃ is O or S. In certain embodiments, the compoundhaving structure (IV) is selected from the group consisting of

In other embodiments, there is provided a compound having the structure(V) or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceuticallyacceptable salt thereof:

wherein:

-   -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, —NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, and —CONR₆R₇, wherein R₆ and R₇ are        independently selected from a group consisting of hydrogen, and        an optionally substituted C₁-C₆ alkyl; n is 1 or 2; and    -   R₁₄ is selected from a group consisting of an optionally        substituted C₁-C₁₂ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, and an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms.

In certain embodiments, the compound having structure (V) is selectedfrom the group consisting of

A carbon-hydrogen bond is by nature a covalent chemical bond. Such abond forms when two atoms of similar electronegativity share some oftheir valence electrons, thereby creating a force that holds the atomstogether. This force or bond strength can be quantified and is expressedin units of energy, and as such, covalent bonds between various atomscan be classified according to how much energy must be applied to thebond in order to break the bond or separate the two atoms.

The bond strength is directly proportional to the absolute value of theground-state vibrational energy of the bond. This vibrational energy,which is also known as the zero-point vibrational energy, depends on themass of the atoms that form the bond. The absolute value of thezero-point vibrational energy increases as the mass of one or both ofthe atoms making the bond increases. Since deuterium (D) is two-foldmore massive than hydrogen (H), it follows that a C-D bond is strongerthan the corresponding C—H bond. Compounds with C-D bonds are frequentlyindefinitely stable in H₂O, and have been widely used for isotopicstudies. If a C—H bond is broken during a rate-determining step in achemical reaction (i.e. the step with the highest transition stateenergy), then substituting a deuterium for that hydrogen will cause adecrease in the reaction rate and the process will slow down. Thisphenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE) andcan range from about 1 (no isotope effect) to very large numbers, suchas 50 or more, meaning that the reaction can be fifty, or more, timesslower when deuterium is substituted for hydrogen. High DKIE values maybe due in part to a phenomenon known as tunneling, which is aconsequence of the uncertainty principle. Tunneling is ascribed to thesmall size of a hydrogen atom, and occurs because transition statesinvolving a proton can sometimes form in the absence of the requiredactivation energy. A deuterium is larger and statistically has a muchlower probability of undergoing this phenomenon. Substitution of tritiumfor hydrogen results in yet a stronger bond than deuterium and givesnumerically larger isotope effects.

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen andhas molecular weight of 2.0144. The natural abundance of deuterium is0.015%. Thus in all chemical compounds with a H atom, the H atomactually represents a mixture of H and D, with about 0.015% being D.Deuterium-enriched compounds have different molecular weight and/orsizes from their hydrogen counter-parts. Deuteration of pharmaceuticalsto improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicityprofiles, has been demonstrated previously with some classes of drugs.For example, DKIE was used to decrease the hepatotoxicity of halothaneby presumably limiting the production of reactive species such astrifluoroacetyl chloride.

In some embodiments, the invention compounds having the structure (I) to(V) are deuterium-enriched by replacing at least one hydrogen atom withdeuterium atom. In another embodiment, the deuterium enrichment is atleast about 1%.

In certain embodiments, the invention compounds have the structuresIa-Va or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or apharmaceutically acceptable salt thereof:

wherein

-   -   R″ is a H or D,    -   Q is O or S;    -   W is C₆-C₁₂ aryl or C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   each of X and Y is independently absent or is NH;    -   each of Z₁ and Z₂ is independently selected from a group        consisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower        alkyl;    -   Z₃ is O, S or NR₅, wherein R₅ is hydrogen or lower alkyl;    -   R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having        1-3 heteroatoms or an alkyl substituted with an unsubstituted or        a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;    -   each R₂ and R₃ are independently selected from a group        consisting of a hydrogen, a C₁-C₆ alkoxy, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms,        CF₃, halogen, CN, CONHR₆ and CO₂R′ wherein R′ is hydrogen or        C₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form a five        to seven membered carbocycle;    -   R₄ is independently selected from a group consisting of        hydrogen, halogen, C₁-C₆ alkyl, —OH, NO₂, —CN, C₁-C₆ alkoxy,        —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,        —S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently        selected from a group consisting of hydrogen, and an optionally        substituted C₁-C₆ alkyl; and n is 1 or 2;    -   R₈ and R₉ are independently selected from the group consisting        of hydrogen, halogen, optionally substituted C₁-C₆ alkyl, —CF₃,        —OH, optionally substituted C₁-C₆ alkoxy, —NR₁₀R₁₁, and        —SO_(m)R₁₂, wherein R₁₀ and R₁₁ are independently selected from        a group consisting of hydrogen, optionally substituted C₁-C₆        alkyl, —SO₂R₁₂, —S(O)R₁₂, and —COR₁₂, and R₁₂ is an optionally        substituted alkyl or an optional substituted C₃-C₁₂ heteroaryl        having 1-3 heteroatoms and m is 0-2;    -   R₁₃ is an optionally substituted N—(C₁-C₆ alkyl)pyrazolyl or        selected from a group consisting of the following structures:

-   -   R₁₄ is selected from a group consisting of an optionally        substituted C₁-C₁₂ alkyl, an optionally substituted C₃-C₁₂        cycloalkyl, an optionally substituted C₃-C₁₀ heterocycle having        1-3 heteroatoms, an optionally substituted C₆-C₁₂ aryl, and an        optional substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms;        and at least one hydrogen atom of the compound is replaced by        deuterium atom.

In certain embodiments, the compound is selected from the groupconsisting of:

In some embodiments, there are provided pharmaceutical compositionscomprising a compound having the structure (I)-(V) or (Ia)-(Va), in apharmaceutically acceptable carrier.

In other embodiments, there are provided pharmaceutical compositionscomprising a compound having the structure (I)-(V) or (Ia)-(Va), and apharmaceutically acceptable excipient.

In some embodiments, there are provided methods for suppressing,preventing or inhibiting lymphangiogenesis, angiogenesis and/or growthof a tumor. The methods comprise contacting the tumor with a compound ofstructures I-V, Ia-Va or a pharmaceutical composition comprising thecompound of structures I-V or Ia-Va thereof.

Due to the hydrophobic interactions and specific hydrogen bondingrequired for type II inhibition, the allosteric site adjacent to thekinase active site may be utilized to improve specificity over the typeI Inhibitors that interact solely with the active kinase conformation inthe highly conserved hinge region. In certain embodiments, the compoundprovided herein is a selective type II inhibitor of a PDGF receptor orRAF kinase. In certain embodiments, the compound provided herein is anallosteric inhibitor of PDGFRα, PDGFRβ, Flt3, RAF (e.g. A-RAF, B-RAF,C-RAF) and/or c-Kit.

Examples of Methods of Dosing and Treatment Regimens

In one aspect, the compositions containing the compounds of structuresI-V or Ia-Va are administered for prophylactic and/or therapeutictreatments. In therapeutic applications, the compositions areadministered to a human subject (patient) already suffering from adisease, disorder, or condition, in an amount sufficient to cure or atleast partially arrest the symptoms of the disease, disorder, orcondition. Amounts effective for this use will depend on the severityand course of the disease, disorder, or condition, previous therapy, thepatient's health status, weight, and response to the drugs, and thejudgment of the treating physician.

In prophylactic applications, compositions containing the compounds ofstructures I-V or Ia-Va are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. In some embodiments, when used ina patient, effective amounts for this use depend on the severity andcourse of the disease, disorder or condition, previous therapy, thepatient's health status and response to the drugs, and the judgment ofthe treating physician.

In some embodiments, the case wherein the patient's condition does notimprove, upon the doctor's discretion the administration of thecompounds of structures I-V or Ia-Va are administered chronically, thatis, for an extended period of time, including throughout the duration ofthe patient's life in order to ameliorate or otherwise control or limitthe symptoms of the patient's disease, disorder, or condition.

In some embodiments, wherein the patient's status does improve, upon thedoctor's discretion the administration of the compounds of structuresI-V or Ia-Va are given continuously; alternatively, the dose of drugbeing administered is temporarily reduced or temporarily suspended for acertain length of time (i.e., a “drug holiday”). In other embodiments,the length of the drug holiday varies between 2 days and 1 year,including by way of example only, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 10 days, about 12days, about 15 days, about 20 days, about 28 days, about 35 days, about50 days, about 70 days, about 100 days, about 120 days, about 150 days,about 180 days, about 200 days, about 250 days, about 280 days, about300 days, about 320 days, about 350 days, or about 365 days. In furtherembodiments, the dose reduction during a drug holiday is from about 10%to about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's condition has occurred, a maintenancedose is administered if necessary. Subsequently, in other embodiments,the dosage or the frequency of administration, or both, are reduced, asa function of the symptoms, to a level at which the improved disease,disorder or condition is retained. In further embodiments, patientswill, however, require intermittent treatment on a long-term basis uponany recurrence of symptoms.

In other embodiments, the amount of a given agent that corresponds tosuch an amount varies depending upon factors such as the particularcompound, disease, disorder, or condition and its severity, the identity(e.g., weight) of the subject or host in need of treatment, butnevertheless is routinely determined in a manner according to theparticular circumstances surrounding the case, including, e.g., thespecific agent being administered, the route of administration, thecondition being treated, and the subject or host being treated. In someembodiments, however, doses employed for adult human treatment aretypically in the range of about 0.02 to about 5000 mg per day or about 1to about 1500 mg per day. In further embodiments, the desired dose isconveniently presented in a single dose or as divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day.

In some embodiments, the pharmaceutical compositions described hereinare in unit dosage forms suitable for single administration of precisedosages. In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or more compound. in otherembodiments, the unit dosage is in the form of a package containingdiscrete quantities of the formulation. Non-limiting examples arepackaged tablets or capsules, and powders in vials or ampoules. Inanother embodiment, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. In further embodiments,multiple-dose reclosable containers are used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection are presented in unit dosageform, which include, but are not limited to ampoules, or in multi-dosecontainers, with an added preservative.

The daily dosages appropriate for the compounds of structures I-V orIa-Va described herein described herein are from about 0.01 to about 200mg/kg per body weight. An indicated daily dosage in the larger mammal,including, but not limited to, humans, is in the range from about 0.5 mgto about 2000 mg, conveniently administered in divided doses, including,but not limited to, up to four times a day or in extended release form.Suitable unit dosage forms for oral administration include from about 1to about 200 mg active ingredient. The foregoing ranges are merelysuggestive, as the number of variables in regard to an individualtreatment regime is large, and considerable excursions from theserecommended values are not uncommon. In further embodiments, suchdosages are altered depending on a number of variables, not limited tothe activity of the compound used, the disease, disorder, or conditionto be treated, the mode of administration, the requirements of theindividual subject, the severity of the disease, disorder, or conditionbeing treated, and the judgment of the practitioner.

In yet further embodiments, toxicity and therapeutic efficacy of suchtherapeutic regimens are determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, including, but notlimited to, the determination of the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between the toxic and therapeuticeffects is the therapeutic index and in some embodiments is expressed asthe ratio between LD₅₀ and ED₅₀. In other embodiments, the data obtainedfrom cell culture assays and animal studies is used in formulating arange of dosage for use in human. In some embodiments, the dosage ofsuch compounds lies within a range of circulating concentrations thatinclude the ED₅₀ with minimal toxicity. In yet further embodiments, thedosage varies within this range depending upon the dosage form employedand the route of administration utilized.

In some embodiments, there are also provided methods and compositionsfor treating cancer, restenosis, intimal hyperplasia, fibrotic diseasesor angiogenesis-dependent disorder in a human subject. The methodscomprise administering to a patient in need a compound of structures I-Vor Ia-Va or a pharmaceutical composition comprising the compound ofstructures I-V or Ia-Va thereof. In certain embodiments, the compound isan allosteric inhibitor of PDGFRα, PDGFRβ, Flt3, RAF (e.g., A-RAF,B-RAF, C-RAF) and/or c-Kit. In another embodiment, the compound inhibitsthe heterodimerization of B-RAF with C-RAF or C-RAF with C-RAF. Incertain embodiments, the compound is a selective type II inhibitor of aPDGF receptor or RAF kinase. In some embodiments, the invention compoundmodulates A-RAF. In some embodiments, the invention compound inhibitsthe phosphorylation of S338 of C-RAF.

Several structural and sequence homology studies of protein kinasedomains have revealed a consensus of what are the common motifs that arerequired for catalytic activity. In some instances, these compriseresidues that are required for nucleotide (ATP) binding, metal ion(Mg2+) binding and residues required for phosphoryl group transfer.There are 518 known human protein kinases, representing the third mostcommon functional domain. Interestingly, about 10% of the kinome appearto lack at least one of the motifs required for catalysis and have beentermed pseudokinases.

Several studies show that mutations affecting pseudokinase domainsunderlie the dysregulation of catalytic activity of severalclinically-important kinases, including LKB1, Raf and Jak2, by theirpartner pseudokinase regulators, STRAD, KSR and the Jak2 JH2 domain,respectively. These studies provide a link between pseudokiase-mediateddysregulation of signal transduction and a number of diseases includingcancers and blood cell malignancies. Exemplary pseudokinases includeSTRADα, Integrin-linked kinase (ILK), HER3 (in human epidermal growthfamily), VRK3 (vaccinia related kinase 3), kinase suppressor of Ras(KSR), and the like.

In some embodiments, the methods described here for treating cancer in ahuman subject comprising administering to a patient in need of theinvention compound that binds a pseudokinase. In certain embodiments,the pseudokinase is a kinase suppressor of Ras (KSR).

In some embodiments, there are provided a compound of structures I-V,Ia-Va that binds a pseudokinase. In certain embodiments, thepseudokinase is a kinase suppressor of Ras (KSR).

In certain embodiments, the cancer is resistant, refractory ornon-responsive to a type I inhibitor of the protein kinase. In certainembodiments, the cancer is resistant, refractory or non-responsive to apan-RAF kinase drug or an ATP-competitive inhibitor. In certainembodiments, the cancer is resistant, refractory or non-responsive to adrug selected from Sorafenib, PLX4032, XL281, RAF265, 885-A, ZM336372,L-779450, AZ628, AAL881, LBT613, MCP110, 17-DMAG, CI1040,AZD6244/ARRY142886, PD0325901, SB590885, DP3346, and DP2514. In certainembodiments, the cancer is resistant, refractory or non-responsive to aVEGF-targeted therapy. In certain embodiments, the cancer is associatedwith a mutant form of RAF kinase; the mutant form of RAF kinase may be aB-RAF kinase selected from mutant T529I, T529N, G464A, G464E, G464V,G466A, G466E, G466V, G469A, G469E, N581S, E586K, F595L, G596R, L597V,L597R, T599I, V600E, and K601E; alternatively, the mutant form of RAFkinase is C-RAF gatekeeper mutant selected from T421N, and T421I. Incertain embodiments, the cancer is selected from melanoma, breastcancer, colon cancer, pancreatic cancer, lung cancer, kidney cancer, andcolon cancer. The cancer may be characterized by stroma rich tumors. Incertain embodiments, the cancer has a mutant or aberration selected fromN-RAS, H-RAS, K-RAS, B-RAF(V600E), B-RAF/Ras, HER1, p53, PTEN, and PI3K.In certain embodiments, the cancer exhibits up-regulation of theRAF-MEK-ERK pathway. In another embodiment, the compound of structuresI-V or Ia-Va is administered orally to the patient in need. In anotherembodiment, the human subject is also provided with a therapy selectedfrom anti-angiogenic therapy, a molucularyly-targeted therapy (such asthose directed to other kinases (e.g. EGFR, HER2, HER4, MEK, VEGFR,c-MET, PI3K, AKT, etc.)) chemotherapy or radiation therapy. In anotherembodiment, the response of the human subject to the compound ismonitored by inhibition of the phosphorylation of S338 of C-RAF.

In some embodiments, cancers that are treated by the methods providedherein include, but are not limited to: Cardiac:sarcoma (angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma,fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamouscell, undifferentiated small cell, non-small cell, undifferentiatedlarge cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma,stromal), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubularadenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract:kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastom,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor, chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cord(neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia)! ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, endometrioid tumors, celioblastoma, clearcell carcinoma, unclassified carcinoma], granulosa-thecal cell tumors,Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva(squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma,fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cellcarcinoma, botryoid sarcoma [embryonal rhabdomyosarcoma], fallopiantubes (carcinoma); Hematologic: blood (myeloid leukemia [acute andchronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia,myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles, dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

In some embodiments, acute myelocytic leukemia (AML) and/or acutelymphocytic leukemia (ALL) are treated using compounds of structures I-Vor Ia-Va in monotherapy or combination therapy.

Restenosis literally means the reoccurrence of stenosis, a narrowing ofa blood vessel, leading to restricted blood flow. Restenosis usuallyrefers to an artery or other large blood vessel that has becomenarrowed, received treatment to clear the blockage and subsequentlybecome renarrowed. This is usually restenosis of an artery, or otherblood vessel, or possibly a vessel within an organ. Restenosis commonlyresults from balloon angioplasty and/or stent placement resulting ineventual occlusion of arteries by a process described as neointimalhyperplasia (NIH). After arterial injury, an over-proliferation ofvascular smooth muscle cells occurs which has previously been shown tobe dependent on both PDGFRα/β (Englesbe, et al. (2004) J Vasc Surg 39,440-6) and MAPK pathway activation (Li, et al. (2005) Circulation 111,1672-8; Pintucci, et al. (2006) Faseb J 20, 398-400). Therefore, thecombination of PDGFRβ/RAF (e.g. B-RAF) inhibition would be an idealtreatment for NIH. Provided herein compounds of structures I-V or Ia-Vamay be selected PDGFRβ/RAF (e.g. B-RAF) inhibitors. In certainembodiments, the restenosis in accordance with the invention methods isintimal hyperplasia-driven restenosis after vascular injury.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that are associated with the abnormal accumulation of cellsand/or fibronectin and/or collagen and/or increased fibroblastrecruitment and include but are not limited to fibrosis of individualorgans or tissues such as the heart, kidney, liver, joints, lung,pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletaland digestive tract.

Exemplary diseases, disorders, or conditions that involve fibrosisinclude, but are not limited to: Lung diseases associated with fibrosis,e.g., idiopathic pulmonary fibrosis, pulmonary fibrosis secondary tosystemic inflammatory disease such as rheumatoid arthritis, scleroderma,lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis,chronic obstructive pulmonary disease (COPD), scleroderma, chronicasthma, silicosis, asbestos induced pulmonary or pleural fibrosis, acutelung injury and acute respiratory distress (including bacterialpneumonia induced, trauma induced, viral pneumonia induced, ventilatorinduced, non-pulmonary sepsis induced, and aspiration induced); Chronicnephropathies associated with injury/fibrosis (kidney fibrosis), e.g.,glomerulonephritis secondary to systemic inflammatory diseases such aslupus and scleroderma, diabetes, glomerular nephritis, focal segmentalglomerular sclerosis, IgA nephropathy, hypertension, allograft andAlport; Gut fibrosis, e.g., scleroderma, and radiation induced gutfibrosis; Liver fibrosis, e.g., cirrhosis, alcohol induced liverfibrosis, nonalcoholic steatohepatitis (NASH), biliary duct injury,primary biliary cirrhosis, infection or viral induced liver fibrosis(e.g., chronic HCV infection), and autoimmune hepatitis; Head and neckfibrosis, e.g., radiation induced; Corneal scarring, e.g., LASIK(laser-assisted in situ keratomileusis), corneal transplant, andtrabeculectomy; Hypertrophic scarring and keloids, e.g., burn induced orsurgical; and Other fibrotic diseases, e.g., sarcoidosis, scleroderma,spinal cord injury/fibrosis, myelofibrosis, vascular restenosis,atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixedconnective tissue disease, and Peyronie's disease. In certainembodiments, the fibrosis in accordance with the invention methods ispulmonary fibrosis or liver fibrosis.

In one embodiment, compounds of structures I-V or Ia-Va are administeredto a human subject with fibrosis of an organ or tissue or with apredisposition of developing fibrosis of an organ or tissue with one ormore other agents that are used to treat fibrosis. In one aspect, theone or more agents include corticosteroids. In another aspect, the oneor more agents include immunosuppresants. In one aspect, the one or moreagents include B-cell antagonists. In another aspect, the one or moreagents include uteroglobin.

In certain embodiments, there are provided methods for preventinginhibition of ASK1-mediated apoptosis in a cell, sensitizing a cell toan extrinsic stress or inhibiting MEK1/2- and/or ERK1/2-mediatedcellular proliferation or migration. The methods comprise contacting thetumor with a compound of structures I-V or Ia-Va or a pharmaceuticalcomposition comprising the compound of structures I-V or Ia-Va thereof.

RAF kinase is an important convergent point downstream of FGFR andVEGFR2 signaling in endothelial cells and plays a critical role inendothelial cell survival during angiogenesis. The stromal compartmentis a major contributor to angiogenesis and tumor growth. This includespericytes associated with the newly forming endothelium, which stabilizethe vasculature and promote vascularization. PDGFRβ is a receptortyrosine kinase (RTK) that is essential for promoting proper pericytefunction, which stabilizes blood vessels and enables vessel maturation.PDGFRβ signaling potentiates pericyte recruitment to newly formingvessels and the secretion of pro-angiogenic molecules such as VEGFA,FGF2, and Angl in the local microenvironment. This promotes vesselstabilization and remodeling of the immature vascular network to ahighly ordered network. Maintenance of the vascular compartment isdependent upon paracrine loops such as the secretion of PDGF-BB andFGF2, which lead to increased expression of FGFR1 on VSMCs and PDGFRα/βon ECs, respectively. Therefore, the homeostasis of the mural andvascular compartments is critical for efficient angiogenesis. Thusinhibiting these two compartments simultaneously would initiate a potentinhibition of angiogenesis.

In certain embodiments, the compound is an allosteric inhibitor ofPDGFRα, PDGFRβ, Flt3, RAF (e.g., A-RAF, B-RAF, C-RAF) and/or c-Kit. Inanother embodiment, the compound inhibits the heterodimerization ofB-RAF with C-RAF or C-RAF with C-RAF. In certain embodiments, thecompound is a selective type II inhibitor of a PDGF receptor or RAFkinase (e.g. B-RAF kinase). In certain embodiments, the extrinsic stressis selected from hypoxia, chemotherapy, radiotherapy or glucose/nutrientstarvation. In certain embodiments, the compound of structures I-V orIa-Va in accordance with the invention methods blocks VEGF- and/orFGF-stimulated endothelial responses in tumor angiogenesis.

In some embodiments, there are provided methods of inhibiting a proteinkinase comprising contacting the protein kinase with an inhibitoryconcentration of a compound of structures I-V or Ia-Va or apharmaceutical composition comprising the compound of structures I-V orIa-Va thereof.

Certain Pharmaceutical and Medical Terminology

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “antagonist,” as used herein, refers to a molecule such as acompound, which diminishes, inhibits, or prevents the action of anothermolecule or the activity of a receptor site. Antagonists include, butare not limited to, competitive antagonists, non-competitiveantagonists, uncompetitive antagonists, partial agonists and inverseagonists.

Competitive antagonists reversibly bind to receptors at the same bindingsite (active site) as the endogenous ligand or agonist, but withoutactivating the receptor.

Allosteric inhibitors (also known as non-competitive antagonists) bindto a distinctly separate binding site from the agonist, exerting theiraction to that receptor via the other binding site. Non-competitiveantagonists do not compete with agonists for binding. The boundantagonists may result in a decreased affinity of an agonist for thatreceptor, or alternatively may prevent conformational changes in thereceptor required for receptor activation after the agonist binds.

The term “cancer,” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymhatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematological malignancies (such as the leukemias).

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of structures I-V or Ia-Va and a co-agent,are both administered to a patient simultaneously in the form of asingle entity or dosage. The term “non-fixed combination” means that theactive ingredients, e.g. a compound of structures I-V or Ia-Va and aco-agent, are administered to a patient as separate entities eithersimultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The term “pharmaceutical composition” refers to a mixture of a compound(i.e., a compound of structures I-V or Ia-Va described herein) withother chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. The pharmaceutical composition facilitates administration ofthe compound to an organism. Multiple techniques of administering acompound exist in the art including, but not limited to: intravenous,oral, aerosol, parenteral, ophthalmic, pulmonary and topicaladministration.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one embodiment, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Composition/Formulation

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. In specific embodiments, pharmaceuticalcompositions are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound(i.e., a compound of structures I-V or Ia-Va described herein) and apharmaceutically acceptable diluent(s), excipient(s), or carrier(s). Incertain embodiments, the compounds described are administered aspharmaceutical compositions in which a compound (i.e., a compound ofstructures I-V or Ia-Va described herein) is mixed with other activeingredients, as in combination therapy. Encompassed herein are allcombinations of actives set forth in the combination therapies sectionbelow and throughout this disclosure. In specific embodiments, thepharmaceutical compositions include one or more compounds (i.e., acompound of structures I-V or Ia-Va described herein).

A pharmaceutical composition, as used herein, refers to a mixture of acompound (i.e., a compound of structures I-V or Ia-Va described herein)with other chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. In certain embodiments, the pharmaceutical compositionfacilitates administration of the compound to an organism. In someembodiments, practicing the methods of treatment or use provided herein,therapeutically effective amounts of compounds (i.e., compounds ofstructures I-V or Ia-Va described herein) are administered in apharmaceutical composition to a mammal having a disease or condition tobe treated. In specific embodiments, the mammal is a human. In certainembodiments, therapeutically effective amounts vary depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds describedherein are used singly or in combination with one or more therapeuticagents as components of mixtures.

In one embodiment, a compound (i.e., a compound of structures I-V orIa-Va described herein) is formulated in an aqueous solution. Inspecific embodiments, the aqueous solution is selected from, by way ofexample only, a physiologically compatible buffer, such as Hank'ssolution, Ringer's solution, or physiological saline buffer. In otherembodiments, a compound (i.e., a compound of structures I-V or Ia-Vadescribed herein) is formulated for transmucosal administration. Inspecific embodiments, transmucosal formulations include penetrants thatare appropriate to the barrier to be permeated. In still otherembodiments wherein the compounds described herein are formulated forother parenteral injections, appropriate formulations include aqueous ornonaqueous solutions. In specific embodiments, such solutions includephysiologically compatible buffers and/or excipients.

In another embodiment, compounds described herein are formulated fororal administration. Compounds described herein, including a compound(i.e., a compound of structures I-V or Ia-Va described herein), areformulated by combining the active compounds with, e.g.,pharmaceutically acceptable carriers or excipients. In variousembodiments, the compounds described herein are formulated in oraldosage forms that include, by way of example only, tablets, powders,pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries,suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds described herein are formulated into other oraldosage forms. Oral dosage forms include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In specific embodiments,push-fit capsules contain the active ingredients in admixture with oneor more filler. Fillers include, by way of example only, lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In other embodiments, softcapsules, contain one or more active compound that is dissolved orsuspended in a suitable liquid. Suitable liquids include, by way ofexample only, one or more fatty oil, liquid paraffin, or liquidpolyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds described herein are formulated for buccal orsublingual administration. Formulations suitable for buccal orsublingual administration include, by way of example only, tablets,lozenges, or gels. In still other embodiments, the compounds describedherein are formulated for parental injection, including formulationssuitable for bolus injection or continuous infusion. In specificembodiments, formulations for injection are presented in unit dosageform (e.g., in ampoules) or in multi-dose containers. Preservatives are,optionally, added to the injection formulations. In still otherembodiments, the pharmaceutical compositions of a compound (i.e., acompound of structures I-V or Ia-Va described herein) are formulated ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles. Parenteral injectionformulations optionally contain formulatory agents such as suspending,stabilizing and/or dispersing agents. In specific embodiments,pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form. Inadditional embodiments, suspensions of the active compounds are preparedas appropriate oily injection suspensions. Suitable lipophilic solventsor vehicles for use in the pharmaceutical compositions described hereininclude, by way of example only, fatty oils such as sesame oil, orsynthetic fatty acid esters, such as ethyl oleate or triglycerides, orliposomes. In certain specific embodiments, aqueous injectionsuspensions contain substances which increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension contains suitable stabilizers oragents which increase the solubility of the compounds to allow for thepreparation of highly concentrated solutions. Alternatively, in otherembodiments, the active ingredient is in powder form for constitutionwith a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In one aspect, compounds (i.e., compounds of structures I-V or Ia-Vadescribed herein) are prepared as solutions for parenteral injection asdescribed herein or known in the art and administered with an automaticinjector. Automatic injectors, such as those disclosed in U.S. Pat. Nos.4,031,893, 5,358,489; 5,540,664; 5,665,071, 5,695,472 and WO/2005/087297(each of which are incorporated herein by reference for such disclosure)are known. In general, all automatic injectors contain a volume ofsolution that includes a compound (i.e., a compound of structures I-V orIa-Va described herein) to be injected. In general, automatic injectorsinclude a reservoir for holding the solution, which is in fluidcommunication with a needle for delivering the drug, as well as amechanism for automatically deploying the needle, inserting the needleinto the patient and delivering the dose into the patient. Exemplaryinjectors provide about 0.3 mL of solution at about a concentration of0.5 mg to 10 mg of a compound (i.e., a compound of structures I-V orIa-Va described herein) per 1 mL of solution. Each injector is capableof delivering only one dose of the compound.

In still other embodiments, the compounds (i.e., a compound ofstructures I-V or Ia-Va described herein) are administered topically.The compounds described herein are formulated into a variety oftopically administrable compositions, such as solutions, suspensions,lotions, gels, pastes, medicated sticks, balms, creams or ointments.Such pharmaceutical compositions optionally contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

In yet other embodiments, the compounds (i.e., compounds of structuresI-V or Ia-Va described herein) are formulated for transdermaladministration. In specific embodiments, transdermal formulations employtransdermal delivery devices and transdermal delivery patches and can belipophilic emulsions or buffered, aqueous solutions, dissolved and/ordispersed in a polymer or an adhesive. In various embodiments, suchpatches are constructed for continuous, pulsatile, or on demand deliveryof pharmaceutical agents. In additional embodiments, the transdermaldelivery of a compound (i.e., compounds of structures I-V or Ia-Vadescribed herein) is accomplished by means of iontophoretic patches andthe like. In certain embodiments, transdermal patches provide controlleddelivery of a compound (i.e., a compound of structures I-V or Ia-Vadescribed herein). In specific embodiments, the rate of absorption isslowed by using rate-controlling membranes or by trapping the compoundwithin a polymer matrix or gel. In alternative embodiments, absorptionenhancers are used to increase absorption. Absorption enhancers orcarriers include absorbable pharmaceutically acceptable solvents thatassist passage through the skin. For example, in one embodiment,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin.

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound(i.e., a compound of structures I-V or Ia-Va described herein); (2) apenetration enhancer; and (3) an aqueous adjuvant. In addition,transdermal formulations can include additional components such as, butnot limited to, gelling agents, creams and ointment bases, and the like.In some embodiments, the transdermal formulation further include a wovenor non-woven backing material to enhance absorption and prevent theremoval of the transdermal formulation from the skin. In otherembodiments, the transdermal formulations described herein maintain asaturated or supersaturated state to promote diffusion into the skin.

In other embodiments, the compounds of structures I-V or Ia-Va areformulated for administration by inhalation. Various forms suitable foradministration by inhalation include, but are not limited to, aerosols,mists or powders. Pharmaceutical compositions of a compound (i.e.,allosteric kinase inhibitors described herein) are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebuliser, with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Inspecific embodiments, the dosage unit of a pressurized aerosol isdetermined by providing a valve to deliver a metered amount. In certainembodiments, capsules and cartridges of, such as, by way of exampleonly, gelatin for use in an inhaler or insufflator are formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Intranasal formulations are known in the art and are described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each ofwhich is specifically incorporated by reference. Formulations, whichinclude a compound (i.e. a compound of structures I-V or Ia-Va describedherein), which are prepared according to these and other techniqueswell-known in the art are prepared as solutions in saline, employingbenzyl alcohol or other suitable preservatives, fluorocarbons, and/orother solubilizing or dispersing agents known in the art. See, forexample, Ansel, H. C. et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, Sixth Ed. (1995). Preferably these compositions andformulations are prepared with suitable nontoxic pharmaceuticallyacceptable ingredients. These ingredients are found in sources such asREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, astandard reference in the field. The choice of suitable carriers ishighly dependent upon the exact nature of the nasal dosage form desired,e.g., solutions, suspensions, ointments, or gels. Nasal dosage formsgenerally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents mayalso be present. Preferably, the nasal dosage form should be isotonicwith nasal secretions.

For administration by inhalation, the compounds described herein, may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

In still other embodiments, the compounds of structures I-V or Ia-Va areformulated in rectal compositions such as enemas, rectal gels, rectalfoams, rectal aerosols, suppositories, jelly suppositories, or retentionenemas, containing conventional suppository bases such as cocoa butteror other glycerides, as well as synthetic polymers such aspolyvinylpyrrolidone, PEG, and the like. In suppository forms of thecompositions, a low-melting wax such as, but not limited to, a mixtureof fatty acid glycerides, optionally in combination with cocoa butter isfirst melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients is optionally used as suitable and asunderstood in the art. Pharmaceutical compositions comprising a compound(i.e., allosteric kinase inhibitors described herein) may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound(i.e., a compound of structures I-V or Ia-Va described herein) describedherein as an active ingredient. The active ingredient is in free-acid orfree-base form, or in a pharmaceutically acceptable salt form. Inaddition, the methods and pharmaceutical compositions described hereininclude the use of N-oxides, crystalline forms (also known aspolymorphs), as well as active metabolites of these compounds having thesame type of activity. All tautomers of the compounds described hereinare included within the scope of the compounds presented herein.Additionally, the compounds described herein encompass unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein. Inaddition, the pharmaceutical compositions optionally include othermedicinal or pharmaceutical agents, carriers, adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure, buffers, and/orother therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical composition comprising at leastcompound (i.e., a compound of structures I-V or Ia-Va described herein)illustratively takes the form of a liquid where the agents are presentin solution, in suspension or both. Typically when the composition isadministered as a solution or suspension a first portion of the agent ispresent in solution and a second portion of the agent is present inparticulate form, in suspension in a liquid matrix. In some embodiments,a liquid composition includes a gel formulation. In other embodiments,the liquid composition is aqueous.

In certain embodiments, pharmaceutical aqueous suspensions include oneor more polymers as suspending agents. Polymers include water-solublepolymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers. Certain pharmaceutical compositionsdescribed herein include a mucoadhesive polymer, selected from, forexample, carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Pharmaceutical compositions also, optionally include solubilizing agentsto aid in the solubility of a compound (i.e., a compound of structuresI-V or Ia-Va described herein). The term “solubilizing agent” generallyincludes agents that result in formation of a micellar solution or atrue solution of the agent. Certain acceptable nonionic surfactants, forexample polysorbate 80, are useful as solubilizing agents, as canophthalmically acceptable glycols, polyglycols, e.g., polyethyleneglycol 400, and glycol ethers.

Furthermore, pharmaceutical compositions optionally include one or morepH adjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

Additionally, pharmaceutical compositions optionally include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other pharmaceutical compositions include one or more surfactantsto enhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other pharmaceutical compositions may include one or moreantioxidants to enhance chemical stability where required. Suitableantioxidants include, by way of example only, ascorbic acid and sodiummetabisulfite.

In certain embodiments, pharmaceutical aqueous suspension compositionsare packaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers are used, in which case it istypical to include a preservative in the composition.

In alternative embodiments, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers herein. In certainembodiments, organic solvents such as N-methylpyrrolidone are alsoemployed. In additional embodiments, the compounds described herein aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are useful herein. In someembodiments, sustained-release capsules release the compounds for a fewhours up to over 24 hours. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization may be employed.

In certain embodiments, the formulations described herein include one ormore antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Unless defined otherwise, all technical and scientific terms used hereinhave the standard meaning pertaining to the claimed subject matterbelongs. In the event that there are a plurality of definitions forterms herein, those in this section prevail. Where reference is made toa URL or other such identifier or address, it understood that suchidentifiers can change and particular information on the internet cancome and go, but equivalent information can be found by searching theinternet. Reference thereto evidences the availability and publicdissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

Unless otherwise indicated, conventional methods of mass spectroscopy,NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniquesand pharmacology are employed. Unless specific definitions are provided,the standard nomenclature employed in connection with, and the standardlaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry areemployed. In certain instances, standard techniques are used forchemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients. In certainembodiments, standard techniques are used for recombinant DNA,oligonucleotide synthesis, and tissue culture and transformation (e.g.,electroporation, lipofection). In some embodiments, reactions andpurification techniques are performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished or as described herein.

As used throughout this application and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight, branched chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”)hydrocarbon containing from 2-10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens. Insome embodiments, depending on the structure, an alkenyl group is amonoradical or a diradical (i.e., an alkenylene group). In someembodiments, alkenyl groups are optionally substituted. Illustrativeexamples of alkenyl include, but are not limited to, ethenyl,2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl,2-heptenyl, 2-methyl-1-heptenyl, and 3-cecenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Illustrative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkyl” as used herein, means a straight, branched chain, orcyclic (in this case, it would also be known as “cycloalkyl”)hydrocarbon containing from 1-10 carbon atoms. Lower alkyl refers to analkyl containing from 1-6 carbon atoms. Illustrative examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl,n-nonyl, and n-decyl.

The term “C₁-C₆-alkyl” as used herein, means a straight, branched chain,or cyclic (in this case, it would also be known as “cycloalkyl”)hydrocarbon containing from 1-6 carbon atoms. Representative examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, cyclopyl, n-butyl, sec-butyl, tert-butyl, cyclobutyl,n-pentyl, isopentyl, neopentyl, cyclopentyl, and n-hexyl.

The term “cycloalkyl” as used herein, means a monocyclic or polycyclicradical that contains only carbon and hydrogen, and includes those thatare saturated, partially unsaturated, or fully unsaturated. Cycloalkylgroups include groups having from 3 to 10 ring atoms. Representativeexamples of cyclic include but are not limited to, the followingmoieties:

In some embodiments, depending on the structure, a cycloalkyl group is amonoradical or a diradical (e.g., a cycloalkylene group).

The term “cycloalkyl groups” as used herein refers to groups which areoptionally substituted with 1, 2, 3, or 4 substituents selected fromalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano,formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene,mercapto, oxo, —NR_(A)R_(A), and (NR_(A)R_(B))carbonyl.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “carbocyclic” as used herein, refers to a compound whichcontains one or more covalently closed ring structures, and that theatoms forming the backbone of the ring are all carbon atoms

The term “carbocycle” as used herein, refers to a ring, wherein each ofthe atoms forming the ring is a carbon atom. Carbocylic rings includethose formed by three, four, five, six, seven, eight, nine, or more thannine carbon atoms. Carbocycles are optionally substituted.

The term “alkoxyalkyl” as used herein, means at least one alkoxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Illustrative examples of alkoxyalkylinclude, but are not limited to, 2-methoxyethyl, 2-ethoxyethyl,tert-butoxyethyl and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Illustrative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxycarbonylalkyl” as used herein, means an alkoxycarbonylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Illustrative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Illustrative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylthio” or “thioalkoxy” as used herein, means an alkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfur atom. Illustrative examples of alkylthio include, butare not limited to, methylthio, ethylthio, butylthio, tert-butylthio,and hexylthio.

The term “alkylthioalkyl” as used herein, means an alkylthio group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Illustrative examples of alkylthioalkylinclude, but are not limited to, methylthiomethyl, 2-(ethylthio)ethyl,butylthiomethyl, and hexylthioethyl.

The term “alkynyl” as used herein, means a straight, branched chainhydrocarbon containing from 2-10 carbons and containing at least onecarbon-carbon triple bond. In some embodiments, alkynyl groups areoptionally substituted. Illustrative examples of alkynyl include, butare not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, and 1-butynyl.

The term “aromatic” as used herein, refers to a planar ring having adelocalized π-electron system containing 4n+2 π electrons, where n is aninteger. In some embodiments, aromatic rings are formed by five, six,seven, eight, nine, or more than nine atoms. In other embodiments,aromatics are optionally substituted. The term includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of carbonatoms) groups.

The term “aryl” as used herein, refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In some embodiments,aryl rings are formed by five, six, seven, eight, nine, or more thannine carbon atoms. Examples of aryl groups include, but are not limitedto phenyl, naphthalenyl, phenanthrenyl, anthracenyl, fluorenyl, andindenyl.

In some embodiments, the term “aryl” as used herein means an aryl groupthat is optionally substituted with one, two, three, four or fivesubstituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carbonyl, cyano,formyl, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkylene,mercapto, nitro, —NR_(A)R_(A), and (NR_(A)R_(B))carbonyl.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Illustrative examples of arylalkyl include, but arenot limited to benzyl, 2-phenylethyl, -phenylpropyl,1-methyl-3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —COOH group.

The term “cyano” as used herein, means a —CN group.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means a —Cl, —Br, —I or —F.

The term “mercapto” as used herein, means a —SH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “hydroxy” as used herein, means a —OH group.

The term “oxo” as used herein, means a ═O group.

The term “bond” or “single bond” as used herein, refers to a chemicalbond between two atoms, or two moieties when the atoms joined by thebond are considered to be part of larger substructure.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” asused herein, include alkyl, alkenyl, alkynyl and alkoxy structures inwhich at least one hydrogen is replaced with a halogen atom. In certainembodiments in which two or more hydrogen atoms are replaced withhalogen atoms, the halogen atoms are all the same as one another. Inother embodiments in which two or more hydrogen atoms are replaced withhalogen atoms, the halogen atoms are not all the same as one another.The terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl andhaloalkoxy groups, respectively, in which the halo is fluorine. Incertain embodiments, haloalkyls are optionally substituted.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from among x=1, y=1 and x=2, y=0. In someembodiments, when x=2, the alkyl groups, taken together with the N atomto which they are attached, optionally form a cyclic ring system.

The term “amide” as used herein, is a chemical moiety with the formula—C(O)NHR or —NHC(O)R, where R is selected from among hydrogen, alkyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheterocycloalkyl (bonded through a ring carbon). In some embodiments, anamide moiety forms a linkage between an amino acid or a peptide moleculeand a compound described herein, thereby forming a prodrug. In someembodiments, any amine, or carboxyl side chain on the compoundsdescribed herein is amidified.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heterocycloalkyl (bonded through a ringcarbon). In some embodiments, any hydroxy, or carboxyl side chain on thecompounds described herein is esterified.

The terms “heteroalkyl” “heteroalkenyl” and “heteroalkynyl” as usedherein, include optionally substituted alkyl, alkenyl and alkynylradicals in which one or more skeletal chain atoms are selected from anatom other than carbon, e.g., oxygen, nitrogen, sulfur, silicon,phosphorus or combinations thereof.

The term “heteroatom” as used herein refers to an atom other than carbonor hydrogen. Heteroatoms are typically independently selected from amongoxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited tothese atoms. In embodiments in which two or more heteroatoms arepresent, the two or more heteroatoms are all the same as one another, orsome or all of the two or more heteroatoms are each different from theothers.

The term “ring” as used herein, refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and heterocycloalkyls),aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g.,cycloalkyls and heterocycloalkyls). In some embodiments, rings areoptionally substituted. In some embodiments, rings form part of a ringsystem.

As used herein, the term “ring system” refers to two or more rings,wherein two or more of the rings are fused. The term “fused” refers tostructures in which two or more rings share one or more bonds.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. In some embodiments,the polycyclic heteroaryl group is fused or non-fused. Illustrative ofheteroaryl groups include, but are not limited to, the followingmoieties:

In some embodiments, depending on the structure, a heteroaryl group is amonoradical or a diradical (i.e., a heteroarylene group).

The term “unsubstituted or substituted heteroaryl” means heteroarylgroups that are substituted with 0, 1, 2, 3, 4 or 5 substituentsindependently selected from, for example, alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,alkylthioalkyl, alynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,halogen, hydroxyl, hydroxyalkylene, mercapto, sulfinyl, sulfonyl, nitro,amino, amido and other suitable moiety. In some embodiments,substituents are independently selected from halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl (e.g. CF₃), OH, NO₂, CN, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,—NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆, —S(O)₂R₆,—CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently selected from agroup consisting of hydrogen, and an optionally substituted C₁-C₆ alkyl.

The term “heteroarylalkyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Illustrative examples of heteroarylalkylinclude, but are not limited to, pyridinylmethyl.

The term “heterocycloalkyl” or “non-aromatic heterocycle” as usedherein, refers to a non-aromatic ring wherein one or more atoms formingthe ring is a heteroatom. A “heterocycloalkyl” or “non-aromaticheterocycle” group refers to a cycloalkyl group that includes at leastone heteroatom selected from nitrogen, oxygen and sulfur. In someembodiments, the radicals are fused with an aryl or heteroaryl. In someembodiments, heterocycloalkyl rings are formed by three, four, five,six, seven, eight, nine, or more than nine atoms. In some embodiments,heterocycloalkyl rings are optionally substituted. In certainembodiments, heterocycloalkyls contain one or more carbonyl orthiocarbonyl groups such as, for example, oxo- and thio-containinggroups. Examples of heterocycloalkyls include, but are not limited to,lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates,tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups, alsoreferred to as non-aromatic heterocycles, include, but are not limitedto

The term heterocycloalkyl also includes all ring forms of thecarbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides.

The term “heterocycle” refers to heteroaryl and heterocycloalkyl usedherein, refers to groups containing one to four heteroatoms eachselected from O, S and N, wherein each heterocycle group has from 4 to10 atoms in its ring system, and with the proviso that the ring of saidgroup does not contain two adjacent O or S atoms. Herein, whenever thenumber of carbon atoms in a heterocycle is indicated (e.g., C₁-C₆heterocycle), at least one other atom (the heteroatom) must be presentin the ring. Designations such as “C₁-C₆ heterocycle” refer only to thenumber of carbon atoms in the ring and do not refer to the total numberof atoms in the ring. In some embodiments, it is understood that theheterocycle ring has additional heteroatoms in the ring. Designationssuch as “4-6 membered heterocycle” refer to the total number of atomsthat are contained in the ring (i.e., a four, five, or six memberedring, in which at least one atom is a carbon atom, at least one atom isa heteroatom and the remaining two to four atoms are either carbon atomsor heteroatoms). In some embodiments, in heterocycles that have two ormore heteroatoms, those two or more heteroatoms are the same ordifferent from one another. In some embodiments, heterocycles areoptionally substituted. In some embodiments, binding to a heterocycle isat a heteroatom or via a carbon atom. Heterocycloalkyl groups includegroups having only 4 atoms in their ring system, but heteroaryl groupsmust have at least 5 atoms in their ring system. The heterocycle groupsinclude benzo-fused ring systems. An example of a 4-membered heterocyclegroup is azetidinyl (derived from azetidine). An example of a 5-memberedheterocycle group is thiazolyl. An example of a 6-membered heterocyclegroup is pyridyl, and an example of a 10-membered heterocycle group isquinolinyl. Examples of heterocycloalkyl groups are pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of heteroaryl groups are pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. In some embodiments, the foregoing groups, as derivedfrom the groups listed above, are C-attached or N-attached where such ispossible. For instance, in some embodiments, a group derived frompyrrole is pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, in some embodiments, a group derived from imidazole isimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocycle groupsinclude benzo-fused ring systems and ring systems substituted with oneor two oxo (═O) moieties such as pyrrolidin-2-one. In some embodiments,depending on the structure, a heterocycle group is a monoradical or adiradical (i.e., a heterocyclene group).

The heterocycles described herein are substituted with 0, 1, 2, 3, or 4substituents independently selected from alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylthio,alkylthioalkyl, alynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl,halogen, hydroxyl, hydroxyalkylene, mercapto, nitro, amino, and amidomoities.

The term “heterocycloalkoxy” refers to a heterocycloalkyl group, asdefined herein, appended to the parent molecular moiety through analkoxy group.

The term “heterocycloalkylthio” refers to a heterocycloalkyl group, asdefined herein, appended to the parent molecular moiety through analkylthio group.

The term “heterocyclooxy” refers to a heterocycloalkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.

The term “heterocyclothio” refers to a heterocycloalkyl group, asdefined herein, appended to the parent molecular moiety through a sulfuratom.

The term “heteroarylalkoxy” refers to a heteroaryl group, as definedherein, appended to the parent molecular moiety through an alkoxy group.

The term “heteroarylalkylthio” refers to a heteroaryl group, as definedherein, appended to the parent molecular moiety through an alkylthiogroup.

The term “heteroaryloxy” refers to a heteroaryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.

The term “heteroarylthio” refers to a heteroaryl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.

In some embodiments, the term “membered ring” embraces any cyclicstructure. The term “membered” is meant to denote the number of skeletalatoms that constitute the ring. Thus, for example, cyclohexyl, pyridine,pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole,furan, and thiophene are 5-membered rings.

The term “non-aromatic 5, 6, 7, 8, 9, 10, 11 or 12-bicyclic heterocycle”as used herein, means a heterocycloalkyl, as defined herein, consistingof two carbocyclic rings, fused together at the same carbon atom(forming a spiro structure) or different carbon atoms (in which tworings share one or more bonds), having 5 to 12 atoms in its overall ringsystem, wherein one or more atoms forming the ring is a heteroatom.Illustrative examples of non-aromatic 5, 6, 7, 8, 9, 10, 11, or12-bicyclic heterocycle ring include, but are not limited to,2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl,2-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.2.0]heptanyl,4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-azaspiro[2.5]octanyl,5-azaspiro[2.5]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl,4-oxa-7-azaspiro[2.5]octanyl, 2-azabicyclo[2.2.2]octanyl,1,3-diazabicyclo[2.2.2]octanyl, 5-azaspiro[3.5]nonanyl,6-azaspiro[3.5]nonanyl, 5-oxo-8-azaspiro[3.5]nonanyl,octahydrocyclopenta[c]pyrrolyl, octahydro-1H-quinolizinyl,2,3,4,6,7,9a-hexahydro-1H-quinolizinyl, decahydropyrido[1,2-a]azepinyl,decahydro-1H-pyrido[1,2-a]azocinyl, 1-azabicyclo[2.2.1]heptanyl,1-azabicyclo[3.3.1]nonanyl, quinuclidinyl, and1-azabicyclo[4.4.0]decanyl.

The term hydroxyalkylene” as used herein, means at least one hydroxylgroup, as defined herein, is appended to the parent molecular moietythrough an alkylene group, as defined herein. Illustrative examples ofhydroxyalkylene include, but not limited to hydroxymethylene,2-hydroxy-ethylene, 3-hydroxypropylene and 4-hydroxyheptylene.

The term “NR_(A)NR_(B)” as used herein, means two group, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are each independently hydrogen, alkyl,and alkylcarbonyl. Illustrative examples of NR_(A)R_(B) include, but arenot limited to, amino, methylamino, acetylamino, and acetylmethylamino.

The term “(NR_(A)NR_(B))carbonyl” as used herein, means a R_(A)R_(B),group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Illustrative examples of(NR_(A)R_(B))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “NR_(C)NR_(D)” as used herein, means two group, R_(C) andR_(D), which are appended to the parent molecular moiety through anitrogen atom. R_(C) and R_(D) are each independently hydrogen, alkyl,and alkylcarbonyl. Illustrative examples of NR_(C)R_(D) include, but arenot limited to, amino, methylamino, acetylamino, and acetylmethylamino.

The term “(NR_(C)NR_(D))carbonyl” as used herein, means a R_(C)R_(D),group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Illustrative examples of(NR_(C)R_(D))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

As used herein, the term “mercaptyl” refers to a (alkyl)S— group.

As used herein, the term “moiety” refers to a specific segment orfunctional group of a molecule. Chemical moieties are often recognizedchemical entities embedded in or appended to a molecule.

As used herein, the term “sulfinyl” refers to a —S(═O)—R, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bondedthrough a ring carbon).

As used herein, the term “sulfonyl” refers to a —S(═O)₂—R, where R isselected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bondedthrough a ring carbon).

As used herein, the term “O carboxy” refers to a group of formulaRC(═O)O—.

As used herein, the term “C carboxy” refers to a group of formula—C(═O)OR.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH₃.

As used herein, the term “trihalomethanesulfonyl” refers to a group offormula X₃CS(═O)₂— where X is a halogen.

As used herein, the term “isocyanato” refers to a group of formula —NCO.

As used herein, the term “thiocyanato” refers to a group of formula—CNS.

As used herein, the term “isothiocyanato” refers to a group of formula—NCS.

As used herein, the term “S sulfonamido” refers to a group of formula—S(═O)₂NR₂.

As used herein, the term “N sulfonamido” refers to a group of formulaRS(═O)₂NH—.

As used herein, the term “trihalomethanesulfonamido” refers to a groupof formula X₃CS(═O)₂NR—.

As used herein, the term “O carbamyl” refers to a group of formula—OC(═O)NR₂.

As used herein, the term “N carbamyl” refers to a group of formulaROC(═O)NH—.

As used herein, the term “O thiocarbamyl” refers to a group of formula—OC(═S)NR₂.

As used herein, the term “N thiocarbamyl” refers to a group of formulaROC(═S)NH—.

As used herein, the term “C amido” refers to a group of formula—C(═O)NR₂.

As used herein, the term “N amido” refers to a group of formulaRC(═O)NH—.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic heterocycle (bonded through a ring carbon).

The term “substituted” means that the referenced group is optionallysubstituted (substituted or unsubstituted) with one or more additionalgroup(s) individually and independently selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone,arylsulfone, cyano, halo, carbonyl, thiocarbonyl, isocyanato,thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy, perhaloalkyl,perfluoroalkyl, silyl, amido, urea, thiourea, and amino, including mono-and di-substituted amino groups, and the protected derivatives thereof.By way of example an optional substituents is L_(s)R_(s), wherein eachL_(s) is independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—,—NHC(O)O—, -(substituted or unsubstituted C₁-C₆ alkyl), or -(substitutedor unsubstituted C₂-C₆ alkenyl); and each R_(s) is independentlyselected from H, (substituted or unsubstituted lower alkyl),(substituted or unsubstituted lower cycloalkyl), heteroaryl, orheteroalkyl.

The term “protecting group” refers to a removable group which modifiesthe reactivity of a functional group, for example, a hydroxyl, ketone oramine, against undesirable reaction during synthetic procedures and tobe later removed. Examples of hydroxy-protecting groups include, but notlimited to, methylthiomethyl, tert-dimethylsilyl,tert-butyldiphenylsilyl, ethers such as methoxymethyl, and estersincluding acetyl, benzoyl, and the like. Examples of ketone protectinggroups include, but not limited to, ketals, oximes, O-substituted oximesfor example O-benzyl oxime, O-phenylthiomethyl oxime,1-isopropoxycyclohexyl oxime, and the like. Examples of amine protectinggroups include, but are not limited to, tert-butoxycarbonyl (Boc) andcarbobenzyloxy (Cbz).

The term “optionally substituted” as defined herein, means thereferenced group is substituted with zero, one or more substituents asdefined herein.

The term “protected-hydroxy” refers to a hydroxy group protected with ahydroxy protecting group, as defined above.

In some embodiments, compounds of the described herein exist asstereoisomers, wherein asymmetric or chiral centers are present.Stereoisomers are designated (R) or (S) depending on the configurationof substituents around the chiral carbon atom. The term (R) and (S) usedherein are configurations as defined in IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, Pure Appl. Chem., (1976),45:13-30, hereby incorporated by reference. The embodiments describedherein specifically includes the various stereoisomers and mixturesthereof. Stereoisomers include enantiomers, diastereomers, and mixturesof enantiomers or diastereomers. In some embodiments, individualstereoisomers of compounds are prepared synthetically from commerciallyavailable starting materials which contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution. Thesemethods of resolution are exemplified by (1) attachment of a mixture ofenantiomers to a chiral axillary, separation of the resulting mixture ofdiastereomers by recrystallization or chromatography and liberation ofthe optically pure product from the auxiliary or (2) direct separationof the mixture of optical enantiomers on chiral chromatographic column.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In some embodiments, the compounds described herein exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Throughout the specification, groups and substituents thereof arechosen, in certain embodiments, to provide stable moieties andcompounds.

EXAMPLE

Even though all three tautomeric structures can exist, all the genericstructures and all the examples having 1,2,4-triazole moiety are shownonly in one tautomeric form, such as 4H-1,2,4-triazole for simplicityand for the comparison with its direct analogues, such as examplescontaining 1,3,4-oxadiazole moiety. The prevailing tautomeric structuredepends on the substituents on the triazole moiety and on the reactionconditions. As has been shown in the literature, 1H-1,2,4-triazole isusually the most common tautomeric form, especially if an aminosubstituent is attached to the ring. Using only 4H-tautomeric form todraw the structures for the sake of simplicity, does not imply that thecompounds of the examples that follow necessarily exist in thatparticular tautomeric form. Using this approach, the IUPAC names for theexamples below are provided for 4H-tautomeric form only, however it isunderstood, that upon the elucidation of the exact tautomeric structurethe numbering of the substituents may differ from the one that isprovided.

Example 1 Synthesis of the 1,2,4-triazole cores

Synthesis of the 1,2,4-triazole cores was carried out as shown in thescheme below. Detailed experimental procedures and analytical datafollow.

Experimental Procedures Step-2: Preparation of Hydroxy Benzohydrazide

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 1 Methyl 3-hydroxybenzoate 152 7 g 46.05 1 2 Hydrazine hydrate 50 23 g 460.4 10 3 Ethanol150 mL

To a stirred solution of methyl 3-hydroxy benzoate (7 g, 46.05 mmol) inethanol (150 mL) was added hydrazine hydrate (23 g, 460.5 mmol) at roomtemperature and the reaction mixture was refluxed for 10-12 hrs. Thereaction was monitored by TLC; upon disappearance of the startingmaterial, the reaction mass was cooled to room temperature and theethanol was distilled out to get the crude product. To this crudeproduct was added acetone (20 mL) at 10-15° C. and this was stirred inn-hexane (100 mL) for 30 min. The white solid that precipitated out wasfiltered and dried under vacuum at 55° C. to obtain the pure product(Yield: 6.9 g, 85.71% of theoretical).

Yield: 95.71%

HPLC Purity: 98.7%

¹H NMR: Consistent with the structure.

LCMS: m/z=153 (MH+)

Step-3: Preparation of 3-(trifluoromethyl) phenyl isothiocyanate

Mol. Molar S. No. Chemical Wt. Amount mmol Ratio 13-(Trifluoromethyl)aniline 161 20 g 124.2 1 2 Thiophosgene 114 21.24186.4 1.5 3 DCM 100 mL 5 Vol.

To a stirred solution of 3-(trifluoromethyl)aniline (20 g, 124.2 mmol)in DCM (100 mL) was added thiophosgene (21.24 g, 186.4 mmol) at 5-10° C.and the reaction mixture was stirred at room temperature for 1-2 h. Thereaction was monitored by TLC (mobile phase-40% ethyl acetate inn-Hexane, Rf. S.M.-0.25, product-0.5). Upon disappearance of thestarting material, the reaction mass was diluted with DCM, the oraniclayer was washed with 10% NaHCO₃, water and brine. The organic layer wasdried and concentrated in vacuo at a temperature lower than 45° C. toafford the product as a yellow oil (Yield: 19.2 g, 76.19% oftheoretical).

Yield: 76.19%

¹H NMR: Consistent with the structure

Step-4: Preparation of (3-trifluoromethyl) phenyl thiourea

Mol. Molar S. No. Chemical Wt. Amount mmol Ratio 1 1-Isothiocyanato-3-203 10 g 49.26 1 (trifluoromethyl)benzene 2 Aq. Ammonia (25%) 17 10.05 g591 12 ~35 mL 3 Methanol 100 mL 10 Vol

To a stirred solution of 1-isothiocyanato-3-(trifluoromethyl)benzene (10g, 49.26 mmol) in Methanol (100 mL) was added aq. ammonia (6.69 g, 394mmol) dropwise at 5° C.-10° C. After complete addition of ammonia, thereaction mixture was stirred at room temperature for 2-3 h. When TLC(mobile phase-40% ethyl acetate in n-Hexane, Rf. S.M.-0.80, product-0.2)showed absence of starting material and formation of product, methanolwas concentrated, water was added and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedto give the pure product as an off-white solid (Yield: 9.2 g, 84.94% oftheoretical).

Yield: 84.94%

HPLC Purity: 99.75%

1H NMR: Consistent with structure

LCMS: MH+: 221 (Mol. Wt. 220)

Step-5: Preparation of the S-Methylisothiourea Hydroiodide Salt

Mol. Molar S. No. Chemical Wt. Amount mmol Ratio 11-(3-(Trifluoromethyl) 220 15 g 68 1 phenyl) thiourea 2 Methyl Iodide148 15.13 g 102 1.5 3 Methanol 150 mL 10 Vol

To a solution of 1-(3-(trifluoromethyl)phenyl)thiourea (15 g, 68 mmol)in methanol (150 mL) was added methyl iodide (15.13 g, 102 mmol)dropwise at room temperature. The reaction mixture was stirred at 50° C.for 7-8 hrs. When TLC (mobile phase-5% methanol in chloroform, Rf.S.M.-0. 30, product-0.2) showed absence of starting material andformation of product, methanol was concentrated to get the pure productas an off white solid (Yield: 22 g, 89.39% of theoretical).

Yield: 89.39%

HPLC Purity: 95.84%,

1H NMR: Consistent with structure

LCMS: MH+: 235 (Mol. Wt. 234)

Step-6: Preparation of the Scaffold—Method 1

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 1 S-Methyl-3- 362 5 g13.81 1 (trifluoromethyl)phenylisothiourea hydroiodide 2 3-Hydroxybenzohydrazide 152 2.32 g 15.26 1.1 3 Pyridine (anhyd.) 30 mL 6 Vol

To a suspension of methyl S-Methyl-3-(trifluoromethyl)phenylisothioureahydroiodide (5 g, 13.81 mmol) in anhydrous pyridine (30 mL) was added3-hydroxy benzohydrazide (2.32 g, 15.26 mmol) under N₂ atmosphere. Aftercomplete addition of hydrazide, the reaction mixture was stirred at 100°C. for 10-12 h. When TLC (mobile phase-10% methanol in chloroform, Rf.S.M.-0. 20, product-0.4) showed absence of starting material, thereaction mixture was cooled to room temperature and the pyridine wasconcentrated under vacuum to get the crude product (yellow oil). Thiswas purified by column chromatography to afford the desired scaffold ina pure form.

Yield: 42.35%

HPLC Purity: 98.08%

1H NMR: Consistent with structure

LCMS: MH+321 (Mol. Wt 320)

Step-6: Preparation of the Scaffold—Method 2

S. Mol. . Molar No. Chemical Wt Amount mmol Ratio 1 S-Methyl-3- 362 6 g16.57 1 (trifluoromethyl)phenyliso- thiourea hydroiodide 2 4-hydroxybenzohydrazide 152 3.02 g 19.8 1.2 3 2,6-Lutidine 107 3.53 g 33 2 4CH₃CN 60 mL 10 Vol

To a suspension of methyl S-Methyl-3-(trifluoromethyl)phenylisothioureahydroiodide (6 g, 16.57 mmole) in Acetonitrile (60 mL) was added2,6-lutidine (3.53 g, 33 mmol) under N₂↑ atmosphere at room temperaturefollowed by 4-hydroxy benzohydrazide (3.02 g, 19.8 mmol) and stirred atroom temperature for 15 min. After complete addition of hydrazidereaction mixture was stirred at 80° C. for 18-20 hrs. When TLC (mobilephase-10% methanol in chloroform, Rf. S.M.-0. 0.20, product-0.5) showedabsence of starting material and formation of product, the mixture wascooled to room temperature and acetonitrile was removed under vacuum.The residue was taken in ethyl acetate and the organic layer was washedwith water (2×), followed by 10% citric acid solution (2×) and finallywith brine. Organic layer was separated and dried over Na₂SO₄ (solid)and concentrated to give crude product. The crude product was purifiedby column chromatography to afford desired product (3.1 g).

Yield: 58.84%

HPLC Purity: 96%.

LCMS: MH+321 (Mol. Wt 320)

Example 2 Synthesis of the 1,3,4-oxadiazole cores

Synthesis of the 1,3,4-oxadiazole cores was carried out as shown in thescheme below.

Experimental Procedures Step-4: Preparation of the Scaffold

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 1 3-Hydroxy 152 1 g 6.51 benzohydrazide 2 1-Isothiocyanato-3- (trifluoromethyl)benzene 203 1.33g 6.5 1 3 DCC 206 1.49 g 7.2 1.1 4 Toluene 5 mL 5 THF 5 mL 6 DMF 5 mL

To a suspension of methyl 3-hydroxy benzohydrazide (1 g, 6.5 mmol) inTHF:Toluene:DMF (5 mL) each was added1-Isothiocyanato-3-(trifluoromethyl)benzene (1.33 g, 6.5 mmol) under N₂↑atmosphere at room temperature. After complete addition ofisothiocyanate reaction mixture was stirred at 80° C. for 30 min. ThenDCC (1.49 g, 7.23 mmol) was added and reaction mixture was stirred at80° C. for 5-6 h. When TLC (mobile phase-5% methanol in chloroform, Rf.S.M.-0. 0.30, product-0.5) showed absence of starting material andformation of product, the reaction mixture was cooled to roomtemperature; water was added and the reaction mixture was extracted withethyl acetate (3×50 mL). The combined organic layer was dried overNa₂SO₄ and concentrated in vacuo to give the crude product. This waspurified by column chromatography to afford desired product (750 mg).

Yield: 35.5%

HPLC Purity: 90.6%

1H NMR: Consistent with structure

LCMS: MH+322 (Mol. Wt 321)

Example 3 Synthesis of the 1,3,4-thiadiazole cores

Synthesis of the 1,3,4-thiadiazole cores was carried out as shown in thescheme below.

Experimental procedures for the synthesis of the 1,3,4-thiadiazole coresStep-2: Preparation ofN-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 1 1-Isothiocyanato-3-203 250 mg 1.23 1 (trifluoromethyl)benzene 2 Hydrazine hydrate 50 308 mg6.16 5 3 Methanol 5 mL

To a stirred solution of 1-isothiocyanato-3-(trifluoromethyl)benzene(250 mg, 1.23 mmol) in methanol (5 mL) was added hydrazine hydrate (307mg, 6.16 mmol) dropwise at 5° C.-10° C. After complete addition ofhydrazine hydrate, the reaction mixture was stirred at room temperaturefor 2-3 h. When TLC (mobile phase-30% ethyl acetate in n-Hexane, Rf.S.M.-0. 80, product-0.2) showed absence of starting material, themethanol was concentrated, water was added and extracted with ethylacetate. The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated to give the pure product as an off white solid(Yield: 200 mg, 69.4% of theoretical).

Yield: 69.4%

LCMS: MH+236 (Mol. Wt. 235)

Step-3: Preparation of the Scaffold

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 1N-(3-(trifluoromethyl) 235 350 mg 1.5 1 phenyl)hydrazine- carbothioamide2 4-Hydroxy benzoic acid 138 246 mg 1.78 1.2 3 POCl₃ 2 mL

A solution of N-(3-(trifluoromethyl)phenyl)hydrazinecarbothioamide (350mg, 1.5 mmol), 4-hydroxy benzoic acid (246 mg, 1.78 mmol) in POCl₃ (2mL) was stirred for 5-6 hrs at 80° C. When TLC (mobile phase-10%methanol in chloroform, Rf. S.M.-0. 20, product-0.5) shows absence ofstarting material and formation product, the reaction mixture was cooledto 10-15° C. and quenched with ice water; the solid that precipitatedwas filtered and dried in Oven at 50° C. the product was purified bycolumn chromatography to obtain an off white solid (Yield: 130 mg, 25.9%of theoretical).

Yield: 25.9%

1H NMR: Consistent with structure

LCMS: MH+338 (Mol. Wt 337)

Example 3 Synthesis of the Inverted Aminotriazole Cores

Synthesis of the 1,2,4-triazole cores was carried out as shown in thescheme below.

Experimental Procedures

Experimental procedures followed were the same as described for thesynthesis of the 1,2,4-triazole cores. Analytical data for theintermediates and the scaffolds are provided below.

(I) Preparation of the Scaffold K43 Step-1: Preparation of the Hydrazide9a

Steps-2 & 3: Preparation of the Thiourea 12a

Step-4: Preparation of the S-Methyl Isothiourea Hydroiodide Salt 6a

Step-5: Preparation of the Scaffold 183

(II) Preparation of the Scaffold K36 Step-4: Preparation of the S-MethylIsothiourea Hydroiodide Salt 13a

Step-5: Preparation of the Scaffold 181

Example 4 Synthesis of the 2-Amino Imidazole Cores

Synthesis of the 2-amino imidazole cores was carried out as shown in thescheme below. Detailed experimental procedures and analytical datafollow.

Experimental procedures for the synthesis of the 2-amino imidazole coreStep-1: Preparation of the Di-Boc Guanidine

S. Mol. mmol No. Chemical Wt. Amount Ratio Molar 1 3-Trifluoro methylaniline 161 81 mg 0.5 1 2 Bis Boc thiourea 276 138 mg 0.5 1 3Mercury(II) Chloride 270 150 mg 0.55 1.1 4 TEA 101 152 mg 1.5 3 5 DCM 5mL

To a suspension of 3-trifluoromethyl aniline (81 mg, 0.5 mmol), bis bocthiourea (138 mg, 0.5 mmol) and Et₃N (152 mg, 1.5 mmol) in DCM was addedmercury(II) chloride (150 mg, 055 mmol) at 0° C. The reaction mixturewas stirred at 0° C. for 1 h and then allowed to warm to roomtemperature and stirred overnight. When TLC (mobile phase-40% ethylacetate in n-Hexane Rf. S.M.-0. 3, product-0.5) shows formation ofproduct with some starting material unreacted, the reaction mixture wasdiluted with ethyl acetate and the inorganic by-product was filteredoff. The organic layer was washed with water (2×25 mL) followed by brine(1×25 mL). The organic layer was dried over Na₂SO₄ and concentrated invacuo to yield the product (200 mg).

Yield: 89.39%

HPLC Purity: 95.38%

1H NMR: Consistent with structure

Step-2: Preparation of 1-(3-(trifluoromethyl)phenyl)guanidine

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 1 Compound-a18 403 806mg 2 1 2 TFA 114 2.28 g 20 10 3 DCM 10 mL

To a suspension of compound a18 (806 mg, 2 mmol) in DCM (10 mL) wasadded TFA (2.28 g, 20 mmol) and the reaction mixture was stirred at roomtemperature overnight. TLC (mobile phase-40% ethyl acetate in n-HexaneRf. S.M.-0. 6, product-0.2) showed absence of starting material andformation of product. Water was added to the reaction mixture andstirred for 15-20 min. The aqueous layer was separated and basified with10% NaHCO₃ solution to pH ˜10. The free base product was extracted withethyl acetate; the combined organic layer was dried over Na₂SO₄ andconcentrated in vacuo to yield the product (350 mg).

Yield: 72.4%

HPLC Purity: 84.04%

1H NMR: Consistent with structure

LCMS: MH+: 338 (Mol. Wt 337)

Step-3: Preparation of 2-amino imidazole scaffold K38

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 11-(3-(trifluoromethyl) 203 456 mg 2.25 1.5 phenyl) guanidine 22-bromo-1-(4- 215 323 mg 1.5 1 hydroxyphenyl)ethanone 3 K₂CO₃ 138 249 mg1.8 1.2 4 THF 20 mL

To a solution of 1-(3-(trifluoromethyl)phenyl) guanidine (456 mg, 2.25mmol) in THF (10 mL) was added K₂CO₃ (249 mg, 1.18 mmol) followed by2-bromo-1-(4-hydroxyphenyl)ethanone (323 mg, 1.5 mmol) at 0° C. Thereaction mixture was allowed to warm to room temperature and stirredovernight. LCMS and TLC (mobile phase: 10% methanol in chloroform, Rf.S.M.-0. 20, product-0.35) formation of product and absence of startingmaterial. The crude product after aqueous workup was purified bypreparative HPLC to afford 120 mg of the scaffold K38.

Yield: 25%

HPLC Purity: 90.6%

1H NMR: Consistent with structure

LCMS: MH+: 338 (Mol. Wt 337)

Example 5 Synthesis of the Exemplary Mercapto Library Compound 119

Synthesis of the mercapto core was carried out as shown in the schemebelow. Detailed experimental procedures and analytical data follow.

Experimental Procedures for the Synthesis of Compound 119 Step-1:Preparation of methyl 4-mercaptobenzoate

S. Molar No. Chemical Mol. Wt. Amount mmol Ratio 1 4-mercapto 154  5 g32.4 1 benzoic acid 2 H₂SO₄ Cat. 3 Methanol 25 mL

To a solution of 4-mercapto benzoic acid (5 g, 32.4 mmol) in methanol(25 mL) was added catalytic H₂SO₄ (1-2 drops) and refluxed for 5-6 h.TLC (mobile phase-10% methanol in chloroform Rf. S.M.-0.2, product-0.6)shows absence of starting material and formation of product; themethanol was distilled off in vacuo and the residue was diluted withethyl acetate. The organic layer was washed with water (2×25 mL)followed by 10% aq. sodium bicarbonate solution. The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to obtained the product asan off-white solid (Yield-5 g).

Yield: 97.7%

HPLC Purity: 97.08%

1H NMR: Consistent with structure

LCMS: MH+: 169 (Mol. Wt. 168)

Step-2: Coupling Reaction of the Mercapto Benzoate and Di-BocChlorovariant

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 1 Methyl 4-mercapto 168500 mg 2.97 1 benzoate 2 Di-Boc 375 1.35 g 3.57 1.2 chlorovariant a23 3K₂CO₃ 138 500 mg 3.57 1.2 4 DMF 10 mL

To a stirred solution of the di-Boc chloro derivative a23 (1.35 g, 3.57mmol) in DMF (10 mL) was added K₂CO₃ (500 mg, 3.57 mmol) and methyl4-mercaptobenzoate (500 mg, 2.97 mmol) at room temperature. The reactionmass was stirred at room temperature for 2-3 h. TLC (mobile phase-40%ethyl acetate in n-hexane Rf. S.M.-0.5, product-0.4) and LCMS showedformation of product and absence of starting material. The reactionmixture was diluted with ethyl acetate (25 mL) and washed with water(3×30 mL) followed by brine. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to afford the desired product (900 mg).

Yield: 60%

HPLC Purity: 92%

LCMS: MH+: 308 (Mol. Wt. 507). Boc deprotected mass

Step-3: Preparation of methyl4-(3-amino-5-(methylthio)phenylthio)benzoate

S. Mol. Molar No Chemical Wt. Amount mmol Ratio 1 Compound a24 507 270mg 0.53 1 2 Trifluoro acetic acid 114 364 mg 3.2 6 3 DCM 10 mL

To a stirred solution of compound a24 (287 mg, 0.53 mmol) in DCM (10 mL)was added trifluoroacetic acid (364 mg, 3.2 mmol) at 5-10° C. Thereaction mass was stirred at room temperature overnight. TLC (mobilephase-10% methanol in chloroform Rf. S.M.-0.5, product-0.2) and LCMSshowed formation of product and absence of starting material. Water wasadded to the reaction mixture and stirred for 15-20 min. The aqueouslayer was separated and basified with 10% NaHCO₃ solution to pH ˜10. Thefree base product was extracted with ethyl acetate; the combined organiclayer was dried over Na₂SO₄ and concentrated in vacuo to yield theproduct (350 mg).

Yield: 73.6%

LCMS Purity: 97.89%

LCMS: MH+: 308 (Mol. Wt. 307)

Step-4: Preparation of4-(3-amino-5-(methylthio)phenylthio)benzohydrazide

S. Mol. Molar No. Chemical Wt. Amount mmol Ratio 1 Compound-a25 307 250mg 0.81 1 2 Hydrazine hydrate 50 325 mg 6.5 8 3 Methanol 10 mL

To a stirred solution of compound a25 (250 mg, 0.81 mmol) in methanol(10 mL) was added hydrazine hydrate (325 mg, 6.5 mmol) at roomtemperature. The reaction mixture was refluxed for 5-6 h. TLC (mobilephase-10% methanol in chloroform Rf. S.M.-0.5, product-0.2) and LCMSshows formation of product and absence of starting material. Thereaction mixture was cooled to room temperature and methanol wasdistilled off in vacuo to get the crude product. This was stirred inn-hexane:acetone (95:05) and the solid that precipitated out wasfiltered to get the product (210 mg).

Yield: 84%

HPLC Purity: 91.3%

LCMS: MH+: 308 (Mol. Wt. 307)

Step-5: Preparation of the Target Molecule 119

S. Molar No. Chemical Mol. Wt. Amount mmol Ratio 1 Compound a26 307 100mg 0.32 1 2 Compound a27 362 129 mg 0.36 1.1 3 Pyridine 5 mL

A solution of compound a26 (100 mg, 032 mmol), compound a27 (129 mg,0.36 mmol) in pyridine (5 mL) was stirred at 80° C. for 6-7 h. TLC(mobile phase-10% methanol in chloroform Rf. S.M.-0.2, product-0.3) andLCMS showed formation of product and absence of starting material. Thereaction mixture was cooled to room temperature. Pyridine was distilledoff in-vacuo and the crude residue obtained was purified by preparativeHPLC to furnish the pure mercapto library compound 119 (60 mg).

Yield: 38.96%

HPLC Purity: 98.71%

1H NMR: Consistent with structure

LCMS: MH+: 308 (Mol. Wt. 307)

Example 6 Library Preparation

Methods of Generation

(A) Compounds Generated by Coupling Reaction of Core and Halovariant:

Most of the targets were generated by coupling of the scaffolds withvarious chlorovariants. The methods used for the coupling reaction havebeen described in brief below.

Coupling was attempted with over 50 halovariants includingpyridine/pyrimidine/quinoline/isoquinoline derivatives. The reactionscheme and the general experimental procedures have been describedbelow.

General procedure for the coupling reaction of halovariants with K1/K2

Method A1 (Conditions (i)):

To a mixture of the scaffold (K1/K2, 160 mg, 0.5 mmol), the halovariant(1.2 equiv., 0.6 mmol) and Cs₂CO₃ (196 mg, 0.6 mmol) was added DMF (0.3mL) and the reaction mixture was heated at 110° C. overnight. H₂O (10mL) was then added to the reaction mixture and extracted with EtOAc(4×20 mL). The combined organic layer was washed with water & brine anddried over Na₂SO₄. Removal of the solvent under reduced pressure yieldeda residue which was purified by preparative HPLC to afford the pureproduct.

Yield & Purity: As mentioned in the Table below.Method A2 (Conditions (ii)):

To a mixture of the scaffold (K1/K2, 160 mg, 0.5 mmol), the halovariant(1.2 equiv., 0.6 mmol) and Cs₂CO₃ (196 mg, 0.6 mmol) was added THF (0.3mL) and the reaction mixture was heated at 65° C. overnight. H₂O (10 mL)was then added to the reaction mixture and extracted with EtOAc (4×20mL). The combined organic layer was washed with water & brine and driedover Na₂SO₄. Removal of the solvent under reduced pressure yielded aresidue which was purified by preparative HPLC to afford the pureproduct.

Yield & Purity: As mentioned in the Table.Method A3 (Conditions (iii)):

To a mixture of the scaffold (K1/K2, 160 mg, 0.5 mmol), the halovariant(1.2 equiv., 0.6 mmol) and Cs₂CO₃ (196 mg, 0.6 mmol) was added DMF (2mL) and the reaction mixture was heated at 200/240° C. under microwaveconditions for 20-30 min. H₂O (10 mL) was then added to the reactionmixture and extracted with EtOAc (4×20 mL). The combined organic layerwas washed with water & brine and dried over Na₂SO₄. Removal of thesolvent under reduced pressure yielded a residue which was purified bypreparative HPLC to afford the pure product.

Yield & Purity: As mentioned in the Table.

(B) Compounds Generated from the Hydrazide Intermediate H3:

Some of the compounds were prepared from the hydrazide intermediate (H3,structure shown below). These have been indicated as “hydrazide route”under the “method of synthesis” column in the table. A general schemefor the synthesis of these compounds is also depicted.

The experimental procedures for the synthesis of the S-methylisothiourea hydroiodide a29 (3-steps from a28 via the correspondingisothiocyanate and thiourea) and for the preparation of the librarycompound (cyclization reaction involving compound a29 and the hydrazideintermediate H3) are the same as described earlier in the synthesis ofthe cores.

(C) Compounds generated by displacement reaction on a 2-pyrimidinyl(sulfoxide or sulfone displacement)

S. Molar No. Chemical Mol. Wt. Amount mmol Ratio 1 Compound 64 491 150mg 0.31 1 2 N-(2- 119 54.5 mg 0.46 1.5 mercaptoethyl)acetamide 3 K₂CO₃138 51.3 mg 0.37 1.2 4 DMF 2.5 mL

To a stirred solution of compound 64 (150 mg, 0.31 mmol) in DMF (2.5 mL)was added K₂CO₃ (51.3 mg, 0.37 mmol) and N-(2-mercaptoethyl)acetamide(54.5 mg, 0.46 mmol) at room temperature and the reaction mixture washeated at 80° C. for 3-4 h. TLC (mobile phase-10% MeOH in CHCl₃) showedabsence of starting material and formation of a new spot. The reactionmixture was cooled to room temperature and water was added and extractedwith ethyl acetate; the organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo to obtain the crude product which waspurified by preparative HPLC (qty.: 40 mg).

Yield: 25%

HPLC Purity: 99.6%

1H NMR: Consistent with structure

LCMS: MH+: 532 (Mol. Wt 531)

Example 7 Cell Viability Assays MTT Assay

MTT assay is used to determine cell proliferation, percent of viablecells, and cytotoxicity. MTT(3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide) is ayellow dye, which can be absorbed by the living cells and be reduced topurplish blue formazan crystals by succinate tetrazolium reductase inmitochondria. Formazan formation can therefore be used to assess anddetermine the survival rate of cells.

Tumor cells (A549) were plated at 2500 cells/well of a 96-well plate incomplete growth medium (DMEM+10% FBS, antibiotic/antimycotic, fungizone,L-glutamine, sodium pyruvate, and non-essential amino acids). The cellswere allowed to grow overnight. After cell proliferation, the cells werewashed and re-suspended in fresh culture medium and placed in 96 wellplates.

To each of the 96 well plates containing A549 and a control, 5, 1, and0.2 μM of the exemplary compounds 1-200 were add. The 96 well plateswere incubated for 48 hours. Cell viability was measured by adding MTT(Sigma) at 5 mg/ml for 4 h to the cells and then removing the medium andresuspending each well in 50 μl DMSO to solubilize the crystals. The96-well plates were read on a plate-scanning spectrophotometer (BioTek)at an absorbance of 560 nm. The survival rate of cells was calculatedbased on the measurement of absorption at the 570 nm wavelength byenzyme immunoassay analyzer. The results are shown in the Table 1.

EC50 of in Cell Viability Assays

Tumor cells (A549) were plated at 2500 cells/well of a 96-well plate incomplete growth medium (DMEM+10% FBS, antibiotic/antimycotic, fungizone,L-glutamine, sodium pyruvate, and non-essential amino acids). The cellswere allowed to grow overnight and then serial dilutions of theexemplary compounds 254-274 in DMSO were added to fresh complete growthmedium and added to the cells for 72 h. Cell viability was measured byadding MTT (Sigma) at 5 mg/ml for 4 h to the cells and then removing themedium and resuspending each well in 50 μl DMSO to solubilize thecrystals. The 96-well plates were read on a plate-scanningspectrophotometer (BioTek) at an absorbance of 560 nm. The 11 pt cellviability curves were plotted using GraphPad software and EC50s werecalculated using the software and the non-linear regression feature. Theresults are shown in the Table 1 below.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

TABLE 1 Exemplary invention compounds and the illustrative results ofcell viability on A549 cells % Viability A549 +: <50% Method % ++:50-70% Formula of Purity +++: >70% Compound Structure Mol. Wt. synthesis(HPLC) 5 μM 1 μM 0.2 μM 1.

C19H14F3N7O 413.36 A1 99.30 ++ ++ +++ 2.

C19H14F3N7O 413.36 A1 99.97 +++ +++ +++ 3.

C20H14F3N5O 397.35 A3 98.60 + ++ +++ 4.

C20H15F3N6O 412.37 A3 96.71 ++ +++ +++ 5.

C20H13ClF3N5O 431.80 A3 97.85 +++ +++ +++ 6.

C20H13ClF3N5O 431.80 A3 99.34 + ++ +++ 7.

C20H15F3N6O3S 476.43 A3 94.56 +++ +++ +++ 8.

C21H13F6N5O 465.35 A3 98.72 ++ +++ +++ 9.

C22H16F3N7OS 483.47 A1 99.32 +++ +++ +++ 10.

C21H14F3N7O 437.38 A3 99.75 ++ +++ +++ 11.

C25H18F3N5O2 477.44 A1 97.05 ++ +++ +++ 12.

C24H16F3N5O 447.41 A3 97.85 ++ +++ +++ 13.

C19H15F3N8O 428.37 A3 99.60 ++ +++ +++ 14.

C20H16F3N7OS 459.50 A3 94.62 ++ ++ ++ 15.

C19H14F3N7O 413.36 A1 99.18 +++ +++ +++ 16.

C19H14F3N7O 413.36 A1 99.60 +++ +++ +++ 17.

C20H14F3N5O 397.35 A3 99.56 ++ ++ +++ 18.

C20H15F3N6O 412.37 A3 98.37 + + ++ 19.

C20H15F3N6O3S 476.43 A3 97.01 +++ +++ +++ 20.

C21H13F6N5O 465.35 A3 95.94 ++ +++ +++ 21.

C21H14F3N7O 437.38 A3 99.36 +++ +++ +++ 22.

C25H18F3N5O2 477.44 A1 96.25 +++ +++ +++ 23.

C24H16F3N5O 447.41 A3 99.28 +++ +++ +++ 24.

C19H14F3N7O2 429.36 A3 99.36 +++ +++ +++ 25.

C20H15F3N6O2S 460.43 A1 99.16 + + + 26.

C19H11ClF3N5O2 433.77 A3 97.08 +++ +++ +++ 27.

C19H13F3N6O2 414.34 A3 96.26 ++ +++ +++ 28.

C19H13F3N6O2 414.34 A1 99.85 +++ +++ +++ 29.

C20H13F3N4O2 398.34 A1 96.35 ++ +++ +++ 30.

C20H12ClF3N4O2 432.78 A3 94.72 ++ +++ +++ 31.

C20H14F3N5O4S 477.42 A3 99.67 +++ +++ +++ 32.

C21H13F3N6O2 438.36 A1 98.77 +++ +++ +++ 33.

C25H17F3N4O3 478.42 A1 99.19 +++ +++ +++ 34.

C24H15F3N4O2 448.40 A3 99.44 +++ +++ +++ 35.

C19H14F3N7O2 429.36 A3 98.93 +++ +++ +++ 36.

C20H15F3N6O2S 460.43 A3 95.31 +++ +++ +++ 37.

C20H13F3N4O2 398.34 A3 97.60 +++ +++ +++ 38.

C20H14F3N5O2 413.35 A3 90.33 +++ +++ +++ 39.

C20H14F3N5O4S 477.42 A1 96.26 +++ +++ +++ 40.

C21H12F6N4O2 466.34 A3 98.90 +++ +++ +++ 41.

C25H17F3N4O3 478.42 A1 99.70 +++ +++ +++ 42.

C24H15F3N4O2 448.40 A3 94.78 +++ +++ +++ 43.

C19H14F3N7OS 445.42 A1 97.22 +++ +++ +++ 44.

C20H15F3N6OS2 476.50 A1 99.95 +++ +++ +++ 45.

C21H13F3N6OS 454.43 A1 98.64 + ++ +++ 46.

C25H17F3N4O2S 494.49 A1 99.55 + +++ +++ 47.

C24H15F3N4OS 464.46 A1 97.69 +++ +++ +++ 48.

C20H15F3N6OS2 476.50 A1 98.46 +++ +++ +++ 49.

C25H17F3N4O2S 494.49 A1 98.72 ++ +++ +++ 50.

C24H15F3N4OS 464.46 A3 98.97 51.

C20H15F3N6O 412.37 A1 96.16 + ++ +++ 52.

C21H18F3N7O2 457.41 A1 94.44 +++ +++ +++ 53.

C22H20F3N7O3 487.43 A1 96.87 + +++ +++ 54.

C20H16F3N7O 427.38 A1 99.98 + + +++ 55.

C20H15F3N6O 412.37 A1 98.35 + ++ ++ 56.

C22H16F3N7OS 483.47 A1 99.98 +++ +++ +++ 57.

C21H18F3N7O2 457.41 A1 99.84 +++ +++ +++ 58.

C22H20F3N7O3 487.43 A1 99.83 +++ +++ +++ 59.

C20H14F3N5O2 413.35 A3 98.39 +++ +++ +++ 60.

C21H13F3N6O2 438.36 A1 99.49 +++ +++ +++ 61.

C21H19F3N8O2 472.42 C 97.15 +++ +++ +++ 62.

C21H19F3N8OS 488.49 C 99.41 +++ +++ +++ 63.

C20H16F3N7O2S 475.45 N.A. 97.98 ++ +++ +++ 64.

C20H16F3N7O3S 491.45 N.A. 94.78 +++ +++ +++ 65.

C20H19N7OS 405.48 B 95.91 ++ +++ +++ 66.

C20H15ClF3N7OS 493.89 B 98.77 + +++ +++ 67.

C21H21N7OS 419.50 B 90.69 + + ++ 68.

C22H15F3N6O 436.39 A3 96.85 + ++ +++ 69.

C24H17F3N6O 462.43 A1 97.30 +++ +++ +++ 70.

C24H17F3N6O2 478.43 A1 90.14 + +++ +++ 71.

C20H15F3N6O2 428.37 A1 96.92 ++ +++ +++ 72.

C20H16F3N7O2 443.38 A1 97.47 + +++ +++ 73.

C21H16F3N5O2 427.38 A3 91.74 + +++ +++ 74.

C21H16F3N5O 411.38 A1 99.51 + + +++ 75.

C22H16F3N7O2 467.40 A1 98.01 +++ +++ +++ 76.

C20H15F3N6O2 428.37 A2 99.37 ++ +++ +++ 77.

C21H18F3N7O 441.41 A1 98.71 ++ ++ +++ 78.

C22H20F3N7O3 487.43 C 98.27 + +++ +++ 79.

C21H18F3N7O2 457.41 A1 98.21 + + +++ 80.

C23H22F3N7OS 501.53 C 99.10 + ++ +++ 81.

C21H18F3N7O 441.41 A1 99.61 + ++ +++ 82.

C20H16F3N7O 427.38 A1 98.21 ++ +++ +++ 83.

C19H13F3N6O 398.34 A1 99.92 +++ +++ +++ 84.

C23H20F3N7O2 483.45 A1 95.21 +++ +++ +++ 85.

C22H15F3N6O 436.39 A3 87.43 ++ +++ +++ 86.

C24H17F3N6O 462.43 A1 91.69 +++ +++ +++ 87.

C24H17F3N6O2 478.43 A1 99.18 +++ +++ +++ 88.

C20H15F3N6O2 428.37 A1 90.36 +++ +++ +++ 89.

C20H16F3N7O2 443.38 A1 91.54 +++ +++ +++ 90.

C21H16F3N5O2 427.38 A3 87.07 +++ +++ +++ 91.

C21H16F3N5O 411.38 A1 91.16 ++ +++ +++ 92.

C22H16F3N7O2 467.40 A1 96.78 +++ +++ +++ 93.

C20H15F3N6O2 428.37 A1 95.56 ++ +++ +++ 94.

C21H18F3N7O 441.41 A1 72.97 ++ +++ +++ 95.

C20H16F3N7O 427.38 A1 97.91 ++ +++ +++ 96.

C22H20F3N7O3 487.43 A1 98.09 +++ +++ +++ 97.

C21H18F3N7O2 457.41 A1 88.32 +++ +++ +++ 98.

C23H22F3N7OS 501.53 A1 83.21 +++ +++ +++ 99.

C21H18F3N7O 441.41 A1 99.90 ++ +++ +++ 100.

C20H16F3N7O 427.38 A1 98.77 +++ +++ +++ 101.

C19H13F3N6O 398.34 A1 96.59 +++ +++ +++ 102.

C21H18F3N7OS 473.47 A1 99.40 +++ +++ +++ 103.

C20H13ClF3N5O 431.80 A1 96.29 ++ +++ +++ 104.

C20H15ClF3N7OS 493.89 A1 96.81 + +++ +++ 105.

C20H15F4N7OS 477.44 A1 98.56 + +++ +++ 106.

C20H15F4N7OS 477.44 A1 96.92 +++ +++ +++ 107.

C20H15F4N7OS 477.44 A1 98.38 ++ +++ +++ 108.

C21H16F3N5O2 427.38 A1 99.04 + +++ +++ 109.

C21H18F3N7O2S 489.47 A1 95.05 + +++ +++ 110.

C22H20F3N7OS 487.50 A1 97.23 +++ +++ +++ 111.

C20H13ClF3N5O 431.80 A1 98.32 +++ +++ +++ 112.

C20H15ClF3N7OS 493.89 A1 95.02 +++ +++ +++ 113.

C24H24F3N7O3S 547.55 C 99.94 1+++ +++ +++ 114.

C23H21F3N8O2S 530.53 C 99.58 +++ +++ +++ 115.

C21H18F3N7O2S 489.47 C 99.73 +++ +++ +++ 116.

C21H16F3N7O3S 503.86 C 96.72 +++ +++ +++ 117.

C22H19F3N8O2S 516.50 C 97.34 +++ +++ +++ 118.

C21H18F3N7OS 473.47 N.A. 98.43 +++ +++ +++ 119.

C20H16F3N7S2 475.51 N.A. 98.71 + + +++ 120.

C21H15F6N7OS 527.45 B 93.64 +++ +++ +++ 121.

C20H18FN7OS 423.47 B 98.14 + ++ +++ 122.

C21H21N7OS 419.50 B 98.90 + +++ +++ 123.

C21H21N7OS 419.50 B 99.38 + + + 124.

C22H21N7OS 431.51 B 93.66 + +++ +++ 125.

C21H21N7OS 419.50 B 95.94 + +++ +++ 126.

C21H21N7OS 419.50 B 92.44 + + + 127.

C20H16N8OS 416.46 B 94.59 ++ +++ +++ 128.

C20H16N8OS 416.46 B 92.45 +++ +++ +++ 129.

C20H22N8O2S 438.51 B 92.68 +++ +++ +++ 130.

C21H18N8OS 430.49 B 95.70 + +++ +++ 131.

C23H22N8OS 458.54 B 98.96 + +++ +++ 132.

C20H23N9OS 437.52 B 96.36 + +++ +++ 133.

C19H16ClN7OS 425.89 B 98.27 + + +++ 134.

C22H23N7O2S 449.53 B 96.06 + +++ +++ 135.

C23H23N7OS 445.54 B 79.48 + + + 136.

C26H21N7OS 479.56 B 96.10 + ++ +++ 137.

C20H15F4N7OS 477.44 B 99.70 + + +++ 138.

C21H19N7O3S 449.49 B 96.82 + +++ +++ 139.

C27H29N9OS 527.64 B 93.44 +++ +++ +++ 140.

C19H16ClN7OS 425.89 B 99.31 ++ +++ +++ 141.

C23H22F3N7OS 501.53 A1 93.81 + +++ +++ 142.

C20H13D3F3N7O2 446.40 N.A. 96.51 +++ +++ +++ 143.

C21H16F3N5O 411.38 Mitsunobu 93.87 +++ +++ +++ 144.

C23H22F3N7OS 501.53 A1 97.01 ++ +++ +++ 145.

C24H24F3N7O2S 531.55 A1 98.74 + +++ +++ 146.

C24H16F3N5O 447.41 A3 91.30 + +++ +++ 147.

C21H13F4N5O3 459.35 N.A. 99.29 ++ +++ +++ 148.

C25H15F6N5O 515.41 A1 95.77 +++ +++ +++ 149.

C24H16F3N5O 447.41 A1 97.87 ++ +++ +++ 150.

C24H15ClF3N5O 481.86 A1 93.88 +++ +++ +++ 151.

C23H22F3N7OS 501.53 A1 99.51 +++ +++ +++ 152.

C24H17F3N8OS 522.50 C 99.03 +++ +++ +++ 153.

C20H17N7O3S 435.46 B 93.41 +++ +++ +++ 154.

C20H19N7OS 405.48 B 94.63 + + ++ 155.

C19H23N7OS 397.50 B 77.11 + +++ +++ 156.

C21H15F4N5O 429.37 Reduction of K1-99 (Raney Ni) 98.46 ++ +++ +++ 157.

0 C22H16F6N6O 494.39 A1 99.90 +++ +++ +++ 158.

C25H18F3N5O 461.44 A1 99.68 ++ +++ +++ 159.

C25H15F6N5O 515.41 A1 99.72 ++ +++ +++ 160.

C25H19F3N6O3 508.45 A1 89.18 ++ +++ +++ 161.

C25H18F3N5O2 477.44 A1 70.91 + ++ +++ 162.

C25H18F3N5O 461.44 A1 97.14 +++ +++ +++ 163.

C25H15F6N5O2 531.41 A1 99.14 +++ +++ +++ 164.

C24H16F3N5O 447.41 A3 93.64 ++ +++ +++ 165.

C25H15F6N5O 515.41 A1 93.65 +++ +++ +++ 166.

C24H16F3N5O 447.41 A1 98.49 +++ +++ +++ 167.

C24H15ClF3N5O 481.86 A1 89.33 +++ +++ +++ 168.

C25H18F3N5O 461.44 A1 99.56 ++ +++ +++ 169.

C25H15F6N5O 515.41 A1 98.88 +++ +++ +++ 170.

C25H19F3N6O3 508.45 A1 96.10 +++ +++ +++ 171.

C25H18F3N5O2 477.44 A1 83.65 +++ +++ +++ 172.

C25H18F3N5O 461.44 A1 98.21 ++ +++ +++ 173.

C25H15F6N5O2 531.41 A1 95.54 +++ +++ +++ 174.

C20H14F3N5O 397.35 A1 99.71 +++ +++ +++ 175.

C25H18F3N5O2 477.44 A1 91.69 +++ +++ +++ 176.

C20H16F3N7OS 459.45 A1 97.29 +++ +++ +++ 177.

C21H16F3N5O 411.38 A1 99.67 +++ +++ +++ 178.

C21H16F3N5O 411.38 A1 99.99 + + ++ 179.

C21H18F3N7OS 473.47 A1 95.27 ++ +++ +++ 180.

C19H16ClN7OS 425.89 A1 97.32 ++ +++ +++ 181.

C15H11F3N4O 320.27 Core synthesis 93.97 +++ +++ +++ 182.

C14H11ClN4O 286.72 Core synthesis 97.45 +++ +++ +++ 183.

C16H13F3N4O 334.30 Core synthesis 99.74 +++ +++ +++ 184.

C25H18F3N5O2 477.44 A1 96.53 ++ +++ +++ 185.

C25H18F3N5O2 477.44 A1 97.95 +++ +++ +++ 186.

C24H15F4N5O 465.40 A1 99.67 +++ +++ +++ 187.

C31H22F3N5O2 553.53 A1 99.79 +++ +++ +++ 188.

C26H20F3N5O2 491.46 A1 96.96 +++ +++ +++ 189.

C25H15F3N6O 472.42 A1 99.54 +++ +++ +++ 190.

C26H21F3N6O 490.48 A1 97.65 ++ +++ +++ 191.

C25H18F3N5O2 477.44 A1 98.80 +++ +++ +++ 192.

C24H15F4N5O 465.40 A1 98.96 +++ +++ +++ 193.

C31H22F3N5O2 553.53 A1 96.51 +++ +++ +++ 194.

C26H20F3N5O2 491.46 A1 98.87 +++ +++ +++ 195.

C25H15F3N6O 472.42 A1 99.57 +++ +++ +++ 196.

C26H21F3N6O 490.48 A1 98.74 ++ +++ +++ 197.

C26H20F3N5O2 491.46 A1 95.06 +++ +++ +++ 198.

C24H18ClN5O2 443.89 A1 97.88 +++ +++ +++ 199.

C21H17F3N6OS 458.46 A1 98.86 + + + 200.

C26H19F3N4O2 476.45 A1 98.05 +++ +++ +++ 201.

C19H15F3N8O 428.37 202.

C19H14F3N7O 413.36 203.

C22H20F3N7O3 487.43 204.

C22H19F3N6O3 472.42 205.

C21H18F3N7O2 457.41 206.

C21H17F3N6O2 442.39 207.

C23H22F3N7O2 485.46 208.

C23H21F3N6O2 470.45 209.

C20H13F6N7O2 497.35 210.

C20H12F6N6O2 482.34 211.

C20H15F3N6O 412.37 212.

C23H20F3N7O 467.45 213.

C21H18F3N7O 441.41 214.

C21H17F3N6O 426.39 215.

C19H15F3N8O 428.37 216.

C19H14F3N7O 413.36 217.

C22H20F3N7O3 487.43 218.

C22H19F3N6O3 472.42 219.

C21H18F3N7O2 457.41 220.

C21H17F3N6O2 442.39 221.

C23H22F3N7O2 485.46 222.

C23H21F3N6O2 470.45 223.

C20H13F6N7O2 497.35 224.

C20H12F6N6O2 482.34 225.

C20H15F3N6O 412.37 226.

C23H20F3N7O 467.45 227.

C21H18F3N7O 441.41 228.

C21H17F3N6O 426.39 229.

C24H18F3N7O 477.44 230.

C23H16F3N7O 463.41 231.

C24H18F3N7O 477.44 232.

C23H16F3N7O 463.41 233.

C24H18F3N7OS 509.51 234.

C23H17F3N8OS 510.49 235.

C23H17F3N8O 478.43 236.

C22H16F3N9O 479.42 237.

C20H17F3N8OS 474.46 238.

C20H17F3N8OS 474.46 239.

C20H17F3N8O2 458.40 240.

C20H17F3N8O2 458.40 241.

C29H28N10OS 564.66 242.

C29H28N10O2S 580.66 243.

C28H28N10OS 552.65 244.

C25H19F3N6O 476.45 245.

C24H17F3N6O 462.43 246.

C25H19F3N6O 476.45 247.

C19H10D4F3N7O 417.38 248.

C19D14F3N7O 427.44 249.

C20H9D7F3N7OS 466.49 250.

C19H10D4F3N7O2 433.38 251.

C19H5D9F3N7O2 438.41 252.

C20H12D3F3N6OS2 479.52 253.

C20H7D8F3N6OS2 484.55 % Viability A549 Method % >10: *** Formula ofPurity 1-10: ** Compound Structure Mol. Wt. synthesis (HPLC) <1.0: *254.

C22H23N7O2 417.46 B 99.2 * 255.

C22H22FN7O2 435.45 B 100 * 256.

C22H23N7O2 417.46 B 100 *** 257.

C22H23N7O2 417.46 B 99.7 * 258.

C22H22ClN7O2 451.91 B 100 *** 259.

C24H25N7O2 443.50 B 98.5 * 260.

C20H18ClN7O2 423.86 B 93.8 * 261.

C21H19N5O 357.41 B 97.8 * 262.

C21H18FN5O 375.40 B 96.6 * 263.

C21H19N5O 357.41 B 94.1 ** 264.

C21H19N5O 357.41 B 99.3 * 265.

C21H18ClN5O 391.85 B 99.1 *** 266.

C23H21N5O 383.45 B 98.1 * 267.

C19H14ClN5O 363.80 B 98.5 ** 268.

C22H21N5O 371.44 B 100 * 269.

C22H20FN5O 389.43 B 98.0 * 270.

C22H21N5O 371.44 B 100 ** 271.

C22H21N5O 371.44 B 100 * 272.

C22H20ClN5O 405.88 B 98.1 ** 273.

C24H23N5O 397.47 B 96.1 * 274.

C20H16ClN5O 377.83 B 94.9 *

What is claimed is:
 1. A compound having the structure (I) or anN-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceuticallyacceptable salt thereof:

wherein: Q is O or S; W is C₆-C₁₂ aryl or C₃-C₁₂ heteroaryl having 1-3heteroatoms; each of X and Y is independently absent or a NH; each of Z₁and Z₂ is independently selected from a group consisting of CH, N, andNR₅, wherein R₅ is hydrogen or lower alkyl; Z₃ is O, S, N, or NR₅,wherein R₅ is hydrogen or lower alkyl; R₁ is an unsubstituted or asubstituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms or an alkylsubstituted with an unsubstituted or a substituted C₃-C₁₂ heteroarylhaving 1-3 heteroatoms; each R₂ and R₃ are independently selected from agroup consisting of a hydrogen, a C₁-C₆ alkoxy, an optionallysubstituted C₁-C₆ alkyl, an optionally substituted C₃-C₁₂ cycloalkyl, anoptionally substituted C₃-C₁₀ heterocycle having 1-3 heteroatoms, anoptionally substituted C₆-C₁₂ aryl, an optional substituted C₃-C₁₂heteroaryl having 1-3 heteroatoms, CF₃, halogen, CN, CONHR₆ and CO₂R′wherein R′ is hydrogen or C₁-C₆ alkyl; or, optionally, R₂ and R₃ arejoined to form a five to seven membered carbocycle; R₄ is independentlyselected from a group consisting of hydrogen, halogen, C₁-C₆ alkyl, —OH,NO₂, —CN, C₁-C₆ alkoxy, —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆,—S(O)R₆, —S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independentlyselected from a group consisting of hydrogen, and an optionallysubstituted C₁-C₆ alkyl; p=0-4; and n is 1 or
 2. 2. The compound ofclaim 1, wherein Q is S.
 3. The compound of claim 1 or claim 2, whereinn is
 2. 4. The compound of claim 1 or claim 2 or claim 3, wherein Z₃ isO or S.
 5. The compound of any one of claims 1-4, wherein W is C₃-C₁₀heterocycle having 1-3 heteroatoms.
 6. The compound of any one of claims1-4, wherein W is C₆-C₁₂ aryl.
 7. The compound of any one of claims 1-5,wherein Z₃ is O or S; and each R₂ and R₃ are independently selected froma group consisting of a hydrogen, a C₁-C₆ alkoxy, an optionallysubstituted C₁-C₆ alkyl, —CF₃, halogen, —CN, and —CO₂R′ wherein R′ ishydrogen or C₁-C₆ alkyl; or, optionally, R₂ and R₃ are joined to form afive to seven membered carbocycle.
 8. The compound of claim 5, wherein Wis selected from the group consisting of thiophene, pyridine,pyridazine, pyrimidine and pyrazine.
 9. The compound of claim 6, whereinW is phenyl.
 10. The compound of any one of claims 1-9, wherein R₁ is anunsubstituted or a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms.11. The compound of any one of claim 1-10, wherein R₁ is anunsubstituted or a substituted pyridine.
 12. The compound of any one ofclaims 1-10, wherein R₁ is an unsubstituted or a substituted pyrimidine.13. The compound of any one of claims 1-12, wherein R₄ is hydrogen. 14.The compound of claim 11, wherein R₁ is an unsubstituted pyridine or aC₁-C₆ alkyl substituted pyridine.
 15. The compound of any one of claims1-14, wherein each R₂ and R₃ are independently selected from a groupconsisting of a C₁-C₆ alkyl, —CF₃, and halogen, wherein p is 0 or 1 or2; or, optionally, R₂ and R₃ are joined to form a five to seven memberedcarbocycle.
 16. The compound of claim 5, wherein the compound isselected from the group consisting of:


17. The compound of claim 1, wherein the compound having structure (I)is selected from the group consisting of:


18. The compound of claim 1, wherein the compound having structure (I)is selected from the group consisting of:


19. The compound of claim 1, wherein the compound having structure (I)is selected from the group consisting of:


20. The compound of claim 1, having the structure (II)

or an N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceuticallyacceptable salt thereof: wherein R₈ and R₉ is independently selectedfrom the group consisting of hydrogen, halogen, optionally substitutedC₁-C₆ alkyl, —CF₃, —OH, optionally substituted C₁-C₆ alkoxy, —NR₁₀R₁₁,and —SO_(m)R₁₂, wherein R₁₀ and R₁₁ are independently selected from agroup consisting of hydrogen, optionally substituted C₁-C₆ alkyl,—SO₂R₁₂, —S(O)R₁₂, and —COR₁₂, and R₁₂ is an optionally substitutedalkyl or an optional substituted C₃-C₁₂ heteroaryl having 1-3heteroatoms and m is 0-2.
 21. The compound of claim 20, wherein each R₂and R₃ are independently selected from a group consisting of a hydrogen,a C₁-C₆ alkoxy, an optionally substituted C₁-C₆ alkyl, —CF₃, halogen,—CN, and —CO₂R′ wherein R′ is hydrogen or C₁-C₆ alkyl; or, optionally,R₂ and R₃ are joined to form a five to seven membered carbocycle. 22.The compound of claim 20 or claim 21, wherein R₄ is hydrogen.
 23. Thecompound of any one of claims 20-22, wherein R₈ and R₉ are independentlyselected from the group consisting of optionally substituted C₁-C₆alkoxy, —NR₁₀R₁₁, and —SO_(m)R₁₂, and m is 0-2.
 24. The compound of anyone of claims 20-23, wherein R₈ is C₁-C₆ alkoxy or —SR₁₂.
 25. Thecompound of any one of claims 20-24, wherein each R₂ and R₃ areindependently selected from a group consisting of a C₁-C₆ alkyl, —CF₃,and halogen wherein p is 0 or 1 or 2; or, optionally, R₂ and R₃ arejoined to form a five to seven membered carbocycle.
 26. The compound ofclaim 20, wherein the compound having structure (II) is selected fromthe group consisting of


27. The compound of claim 20, therein the compound having structure (II)is selected from the group consisting of


28. The compound of claim 20, therein the compound having structure (II)is selected from the group consisting of


29. The compound of claim 1, having the structure (III) or an N-oxide,N,N′-dioxide, N,N′,N″-trioxide, or a pharmaceutically acceptable saltthereof:

wherein each of Z₁ and Z₂ is independently selected from a groupconsisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower alkyl; andZ₃ is O, S, N, or NR₅, wherein R₅ is hydrogen or lower alkyl.
 30. Thecompound of claim 29, wherein Z₃ is O or S.
 31. The compound of claim 29or claim 30, wherein each R₂ and R₃ are independently selected from agroup consisting of a C₁-C₆ alkyl, —CF₃, and halogen wherein p is 0 or 1or 2; or, optionally, R₂ and R₃ are joined to form a five to sevenmembered carbocycle.
 32. The compound of any one of claims 29-31,wherein R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroaryl having1-3 heteroatoms.
 33. The compound of any one of claim 29-32, wherein R₁is an unsubstituted or a substituted pyridine.
 34. The compound of anyone of claims 29-32, wherein R₁ is an unsubstituted or a substitutedpyrimidine.
 35. The compound of any one of claims 29-34, wherein R₄ ishydrogen.
 36. The compound of claim 33, wherein R₁ is an unsubstitutedpyridine or a C₁-C₆ alkyl substituted pyridine.
 37. The compound ofclaim 29, wherein the compound having structure (III) is selected fromthe group consisting of


38. The compound of claim 29, wherein the compound is

or selected from the group consisting of


39. A compound having the structure (IV) or an N-oxide, N,N′-dioxide,N,N′,N″-trioxide, or a pharmaceutically acceptable salt thereof:

wherein: each of Z₁ and Z₂ is independently selected from a groupconsisting of CH, N, and NR₅, wherein R₅ is hydrogen or lower alkyl; Z₃is O, S, N or NR₅, wherein R₅ is hydrogen or lower alkyl; R₁ is anunsubstituted or a substituted C₃-C₁₂ heteroaryl having 1-3 heteroatomsor an alkyl substituted with an unsubstituted or a substituted C₃-C₁₂heteroaryl having 1-3 heteroatoms; R₄ is independently selected from agroup consisting of hydrogen, halogen, C₁-C₆ alkyl, —OH, —NO₂, —CN,C₁-C₆ alkoxy, —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆, —NH₂, —NR₆R₇, —SR₆, —S(O)R₆,—S(O)₂R₆, —CO₂R₆, —CONR₆R₇, wherein R₆ and R₇ are independently selectedfrom a group consisting of hydrogen, and an optionally substituted C₁-C₆alkyl and n is 1 or 2; and R₁₃ is an optionally substituted N—(C₁-C₆alkyl)pyrazolyl or selected from a group consisting of the followingstructures:


40. The compound of claim 39, wherein n is
 2. 41. The compound of claim39 or claim 40, wherein Z₃ is O or S.
 42. The compound of claim 39,wherein the compound having structure (IV) is selected from the groupconsisting of


43. A compound having the structure (V) or an N-oxide, N,N′-dioxide,N,N′,N″-trioxide, or a pharmaceutically acceptable salt thereof:

wherein: R₁ is an unsubstituted or a substituted C₃-C₁₂ heteroarylhaving 1-3 heteroatoms or an alkyl substituted with an unsubstituted ora substituted C₃-C₁₂ heteroaryl having 1-3 heteroatoms; R₄ isindependently selected from a group consisting of hydrogen, halogen,C₁-C₆ alkyl, —OH, —NO₂, —CN, C₁-C₆ alkoxy, —NHSO₂R₆, —SO₂NHR₆, —NHCOR₆,—NH₂, —NR₆R₇, —SR₆, —S(O)R₆, —S(O)₂R₆, —CO₂R₆, and —CONR₆R₇, wherein R₆and R₇ are independently selected from a group consisting of hydrogen,and an optionally substituted C₁-C₆ alkyl; n is 1 or 2; and R₁₄ isselected from a group consisting of an optionally substituted C₁-C₁₂alkyl, an optionally substituted C₃-C₁₂ cycloalkyl, an optionallysubstituted C₃-C₁₀ heterocycle having 1-3 heteroatoms, an optionallysubstituted C₆-C₁₂ aryl, and an optional substituted C₃-C₁₂ heteroarylhaving 1-3 heteroatoms.
 44. The compound of claim 43, wherein n is 2.45. The compound of claim 43, the compound having structure (V) isselected from the group consisting of


46. A pharmaceutical composition comprising a compound as set forth inany of the preceding claims, in a pharmaceutically acceptable carrier.47. A method for suppressing, preventing or inhibitinglymphangiogenesis, neovascularization, recruitment of periendothelialcells, angiogenesis, hyderproliferative disorder, fibrotic lesion,ocular disorder and/or growth of a tumor, which comprises contacting thetumor with the pharmaceutical composition of claim 46 or a compound ofany of the preceding claims 1-45.
 48. A method for treating cancer,restenosis, intimal hyperplasia, fibrotic diseases orangiogenesis-dependent disorder in a human subject comprisingadministering to a patient in need the pharmaceutical composition ofclaim 46 or a compound according to any one of claims 1-45.
 49. A methodfor preventing inhibition of ASK1-mediated apoptosis in a cell,sensitizing a cell to an extrinsic stress, or inhibiting MEK1/2- and/orERK1/2-mediated cellular proliferation or migration comprisingcontacting the cell with the pharmaceutical composition of claim 46 or acompound according to any one of claims 1-45.
 50. A method forinhibiting phosphorylation of S338 of CRAF and/or RAF dimerizationcomprising contacting the cell with the pharmaceutical composition ofclaim 46 or a compound according to any one of claims 1-45.
 51. A methodof inhibiting a protein kinase comprising contacting the protein kinasewith an inhibitory concentration of a compound according to any one ofclaims 1-45.
 52. The method of claim 51, wherein the protein kinase isselected from A-RAF, B-RAF and C-RAF.
 53. A method of inhibiting RAFkinase mediated signaling in a cell comprising contacting the cell withan inhibitory concentration of a compound according to any one of claims1-45.
 54. The method of claim 53 wherein the cell is characterized byincreased activity of the RAS-RAF-MEK-ERK pathway compared to anon-transformed cell.
 55. The method of claim 53, wherein the cell ischaracterized by an A-RAF, B-RAF, or C-RAF gain-of-function mutation.56. The method of any one of claims 47-55, wherein the compound is aselective type II inhibitor of a PDGF receptor or RAF kinase.
 57. Themethod of any one of claims 47-50, wherein the compound inhibits theheterodimerization of B-RAF with C-RAF or C-RAF with C-RAF.
 58. Themethod of any one of claims 47-50, wherein the compound inhibits thephosphorylation of S338 of C-RAF.
 59. The method of any one of claims47-50, wherein said compound is an allosteric inhibitor of PDGFRα,PDGFRβ, Flt3, A-RAF, B-RAF, C-RAF and/or c-Kit.
 60. The method of claim48, wherein the cancer is resistant, refractory or non-responsive to atype I inhibitor of the protein kinase.
 61. The method of claim 48,wherein the cancer is resistant, refractory or non-responsive to apan-RAF kinase drug or an ATP-competitive inhibitor.
 62. The method ofclaim 48, wherein the cancer is resistant, refractory or non-responsiveto a drug selected from Sorafenib, PLX4032, XL281, RAF265, 885-A,ZM336372, L-779450, AZ628, AAL881, LBT613, MCP110, 17-DMAG, CI1040,AZD6244/ARRY142886, PD0325901, SB590885, DP3346, and DP2514.
 63. Themethod of claim 48, wherein the cancer is resistant, refractory ornon-responsive to a VEGF-targeted therapy.
 64. The method of claim 48,wherein the cancer is associated with a mutant form of RAF kinase. 65.The method of claim 64, wherein the mutant form of RAF kinase is a B-RAFkinase selected from mutant T529I, T529N, G464A, G464E, G464V, G466A,G466E, G466V, G469A, G469E, N581S, E586K, F595L, G596R, L597V, L597R,T599I, V600E, and K601E.
 66. The method of claim 64, wherein the mutantform of RAF kinase is C-RAF gatekeeper mutant selected from T421N, andT421I.
 67. The method of claim 48 wherein the cancer is selected frommelanoma, breast cancer, colon cancer, pancreatic cancer, lung cancer,kidney cancer, and colon cancer.
 68. The method of claim 48, wherein thecancer is characterized by stroma rich tumors.
 69. The method of claim48, wherein the cancer has a mutant or aberration selected from N-RAS,H-RAS, K-RAS, B-RAF(V600E), B-RAF/Ras, HER1, p53, PTEN, and PI3K. 70.The method of claim 48, wherein the cancer exhibits up-regulation of theRAF-MEK-ERK pathway.
 71. The method of claim 48, wherein the compound isadministered orally to the patient in need.
 72. The method of claim 48,wherein the human subject is also provided with a therapy selected fromanti-angiogenic therapy, chemotherapy or radiation therapy.
 73. Themethod of claim 48, wherein the response of the patient to the compoundis monitored by inhibition of the phosphorylation of S338 of C-RAF. 74.The method of claim 49 wherein the stress is selected from hypoxia,chemotherapy, radiotherapy or glucose/nutrient starvation.
 75. Themethod of claim 49, wherein the compound blocks VEGF- and/orFGF-stimulated endothelial responses in tumor angiogenesis.
 76. Themethod of claim 48 wherein the restenosis is intimal hyperplasia-drivenrestenosis after vascular injury.
 77. The method of claim 48, whereinthe fibrosis is pulmonary fibrosis.
 78. The method of claim 48, whereinthe fibrosis is liver fibrosis.
 79. The method of claim 48, wherein thefibrosis is cardiac fibrosis.
 80. The compound according to any one ofclaims 1 to 45, wherein said compound is deuterium-enriched by replacingat least one hydrogen atom with deuterium atom.
 81. The compound ofclaim 80, wherein deuterium enrichment is at least about 1%.
 82. Thecompound of claim 80, wherein said compound is selected from the groupconsisting of: